Mitotic kinesin inhibtors and methods of use thereof

ABSTRACT

This invention relates to inhibitors of mitotic kinesins, particularly KSP, and methods for producing these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing the inhibitors and pharmaceutical compositions in the treatment and prevention of various disorders.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a Continuation application of U.S. Ser. No.14/031,958, filed Sep. 19, 2013, which is a Divisional application ofU.S. Ser. No. 13/586,355, filed Aug. 15, 2012, now U.S. Pat. No.8,580,828, which is a Divisional application of U.S. Ser. No.12/822,066, filed Jun. 23, 2010, now U.S. Pat. No. 8,268,871, which is aDivisional application of U.S. Ser. No. 11/415,455, filed May 1, 2006,now U.S. Pat. No. 7,795,282, and claims priority to U.S. ProvisionalApplication Ser. No. 60/676,890, filed May 2, 2005, which areincorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel inhibitors of mitotic kinesins, inparticular the mitotic kinesin KSP, and pharmaceutical compositionscontaining the inhibitors. The compounds of this invention are usefulfor the treatment of cellular proliferative diseases, for examplecancer, hyperplasias, restenosis, cardiac hypertrophy, immune disorders,fungal infections and inflammation. This invention also provides methodsfor preparing these inhibitors.

2. Description of the State of the Art

Among the therapeutic agents used to treat cancer are the taxanes andvinca alkaloids, which act on microtubules. Microtubules are the primarystructural elements of the mitotic spindle, which is responsible fordistribution of replicate copies of the genome to each of the twodaughter cells that result from cell division. It is presumed thatdisruption of the mitotic spindle by these drugs results in inhibitionof cancer cell division and induction of cancer cell death. However,microtubules form other types of cellular structures, including tracksfor intracellular transport in nerve processes. Because drugs such astaxanes and vinca alkaloids do not specifically target mitotic spindles,they have side effects that limit their usefulness.

Improvements in the specificity of agents used to treat cancer is ofconsiderable interest, in part because of the improved therapeuticbenefits which would be realized if the side effects associated withadministration of these agents could be reduced.

Traditionally, dramatic improvements in the treatment of cancer havebeen associated with identification of therapeutic agents acting throughnovel mechanisms. Examples include not only the taxanes, but also thecamptothecin class of topoisomerase I inhibitors. From both of theseperspectives, mitotic kinesins are attractive targets for newanti-cancer agents.

Mitotic kinesins are enzymes essential for assembly and function of themitotic spindle, but are not generally part of other microtubulestructures such as nerve processes. Mitotic kinesins play essentialroles during all phases of mitosis. These enzymes are “molecular motors”that transform energy released by hydrolysis of ATP into mechanicalforce which drives the directional movement of cellular cargoes alongmicrotubules. The catalytic domain sufficient for this task is a compactstructure of approximately 340 amino acids. During mitosis, kinesinsorganize microtubules into the bipolar structure that is the mitoticspindle. Kinesins mediate movement of chromosomes along spindlemicrotubules, as well as structural changes in the mitotic spindleassociated with specific phases of mitosis. Experimental perturbation ofmitotic kinesin function causes malformation or dysfunction of themitotic spindle, frequently resulting in cell cycle arrest and celldeath.

Among the identified mitotic kinesins is kinesin spindle protein (KSP).KSP belongs to an evolutionarily conserved kinesin subfamily of plusend-directed microtubule motors that assemble into bipolar homotetramersconsisting of antiparallel homodimers. During mitosis, KSP associateswith microtubules of the mitotic spindle. Microinjection of antibodiesdirected against KSP into human cells prevents spindle pole separationduring prometaphase, giving rise to monopolar spindles and causingmitotic arrest and induction of programmed cell death. KSP and relatedkinesins in other non-human organisms bundle antiparallel microtubulesand slide them relative to one another, thus forcing the spindle polesapart. KSP may also mediate in anaphase B spindle elongation andfocusing of microtubules at the spindle pole.

Human KSP or HsEg5 has been described (Blangy, et al., Cell, 83:1159-69(1995); Whitehead, et al., Arthritis Rheum., 39:1635-42 (1996); Galtio,et al., J. Cell Biol., 135:339-414 (1996); Blangy, et al., J. Bio.Chem., 272:19418-24 (1997); Blangy, et al., Cell Motil Cytoskeleton,40:174-82 (1998); Whitehead and Rattner, J. Cell Sci., 111:2551-61(1998); Kaiser, et al., JBC 274:18925-31 (1999); GenBank accessionnumbers: X85137, NM004523 and U37426), and a fragment of the KP gene(TRIPS) has been described (Lee, et al., Mol. Endocrinol., 9:243-54(1995); GenBank accession number L40372). Xenopus KSP homologs (Eg5), aswell as Drosophilia K-LP61 F/KRP 130 have been reported.

Small molecule inhibitors of KSP have recently been described in WO03/079,973 and WO 2005/035512.

Mitotic kinesins are therefore attractive targets for the discovery anddevelopment of novel mitotic chemotherapeutics.

SUMMARY OF THE INVENTION

This invention provides novel compounds that inhibit mitotic kinesins,in particular the mitotic kinesin KSP. The compounds of this inventionhave utility as therapeutic agents for diseases that can be treated bythe inhibition of the assembly and function of microtubule structures,including the mitotic spindle.

In general, the invention relates to kinesin inhibitors of the generalFormula I:

and metabolites, solvates, tautomers, and pharmaceutically acceptablesalts and prodrugs thereof, wherein W, Ar¹, Ar², R¹ and R⁴ are asdefined below.

In a further aspect the present invention provides methods of modulatingmitotic spindle formation, which comprises administering to awarm-blooded animal an effective amount of a compound of Formula I, or asolvate, pharmaceutically acceptable salt or pharmaceutically acceptableprodrug thereof.

In a further aspect the present invention provides a method of treatingabnormal cell growth conditions in a human or animal, which comprisesadministering to a warm-blooded animal an effective amount of a compoundof Formula I, or a solvate, pharmaceutically acceptable salt orpharmaceutically acceptable prodrug thereof.

In a further aspect the present invention provides a method ofinhibiting abnormal cell growth, which comprises administering to saidabnormal cells an effective amount of a compound of Formula I, or asolvate, pharmaceutically acceptable salt or pharmaceutically acceptableprodrug thereof.

In a further aspect the present invention provides a method of providinga mitotic kinesin inhibitory effect in a human or animal, comprisingadministering to said human or animal an effective amount of a compoundof Formula I, or a solvate, pharmaceutically acceptable salt orpharmaceutically acceptable prodrug thereof.

In a further aspect the present invention provides methods of treatingor preventing a microtubule-mediated condition in a human or animal,comprising administering to a human or animal in need thereof a compoundof Formula I or a solvate, pharmaceutically acceptable salt orpharmaceutically acceptable prodrug thereof, in an amount effective totreat or prevent said microtubule-mediated condition.Microtubule-mediated conditions that can be treated or preventedaccording to the methods of this invention include, but are not limitedto, cellular proliferative diseases, for example cancer, hyperplasias,restenosis, cardiac hypertrophy, immune disorders, infectious disease,fungal or other eukaryote infections, and inflammatory disease.

The compounds of the present invention may be used advantageously incombination with other known therapeutic agents.

The invention also relates to pharmaceutical compositions comprising acompound of Formula I or a solvate, pharmaceutically acceptable prodrugor pharmaceutically acceptable salt thereof, alone or in combinationwith a second therapeutic agent.

This invention also provides compounds of Formula I for use in therapy.

An additional aspect of the invention is the use of a compound ofFormula I for the preparation of a medicament for use as a kinesininhibitor.

This invention further provides kits comprising compounds of Formula I.

Additional advantages and novel features of this invention shall be setforth in part in the description that follows, and in part will becomeapparent to those skilled in the art upon examination of the followingspecification or may be learned by the practice of the invention. Theadvantages of the invention may be realized and attained by means of theinstrumentalities, combinations, compositions, and methods particularlypointed out in the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of Formula I are useful for inhibiting mitotic kinesinsand microtubule-mediated events such as mitotic spindle production. Suchcompounds have utility for treating or inhibiting a microtubule-mediatedcondition in a human or animal.

In general, the invention relates to compounds of the general Formula I:

and metabolites, solvates, tautomers, salts and pharmaceuticallyacceptable salts and prodrugs thereof, wherein:

W is S(O)_(m);

m is 0, 1 or 2;

R¹ is H, alkyl, cycloalkyl, heteroalkyl, alkenyl or alkynyl, whereinsaid alkyl, cycloalkyl, heteroalkyl, alkenyl and alkynyl are optionallysubstituted with one or more groups independently selected from oxo,halogen, cyano, nitro, azido, —OR¹⁰, —NR¹⁰R¹¹, —NR¹⁰SO₂R¹³, —C(═O)R¹⁰,—OC(═O)R¹⁰, —C(═O)OR¹⁰, —C(═O)NR¹⁰R¹¹, —NR¹⁰C(O)OR¹³,—NR¹⁰C(═O)(CH₂)₀₋₂R¹¹, —SR¹⁰, —S(O)R¹³, —SO₂R¹³, —SO₂NHC(═O)R¹⁰,—NR¹⁰C(O)NR¹¹R¹², alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, —OP(═O)(OR¹⁰)₂, an amino acid residue,a dipeptide, a tripeptide, or —NR¹⁰CR²²R²³NR¹¹R¹², with the proviso thatsaid alkyl does not terminate with a —C(═O)ORo group,

or R¹ is Z—NR¹⁷—C(═NR¹⁸)R¹⁹, Z—NR¹⁷—C(═NR¹⁸)NR²⁰R²¹, Z—C(═NR¹⁸)NR²⁰R²¹,Z—O—NR¹⁷C(═NR¹⁸)NR²⁰R²¹, Z—O—NR¹⁷—C(═NR¹⁸)R²⁰, Z—NR²²—NR²³—C(═NR¹⁸)R¹⁹,or Z—NR²²NR²³—C(═NR¹⁸)NR²⁰R²¹, wherein Z is alkylene optionallysubstituted with one or more halogen;

Ar¹ and Ar² are independently phenyl or a 5 or 6 membered heteroarylring having 1 to 3 heteroatoms independently selected from N, O and S,wherein said heteroaryl is a carbon radical and said phenyl andheteroaryl are optionally substituted with one or more groupsindependently selected from halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —OR¹⁰, —NR¹⁰R¹¹, —NR¹⁰SO₂R¹³,—SO₂NR¹⁰R¹¹, —C(═O)R¹⁰, —C(═O)OR¹⁰, —OC(═O)R¹⁰, —NR¹⁰C(═O)OR¹³,—NRLOC(═O)R¹¹, —C(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹³, SO₂R¹³, —SO₂NHC(═O)R¹⁰,—NR¹⁰C(═O)NR¹¹R¹², —NR¹⁰C(NCN)NR¹¹R¹², —NR¹⁰C(H)NR¹¹R¹²,—NR¹⁰C(R¹³)NR¹¹R¹², —OP(═O)(OR¹⁰)₂, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl;

R⁴ is a partially unsaturated or fully unsaturated 5 memberedheterocyclic ring comprising 1-4 heteroatoms independently selected fromN, O or S,

or R⁴ is a partially unsaturated or fully unsaturated 6 memberedheterocyclic ring comprising 1-4 heteroatoms independently selected fromN, O or S,

or R⁴ is a partially unsaturated or fully unsaturated 7-12 memberedbicyclic heterocyclic ring comprising two or more heteroatomsindependently selected from N, O or S,

wherein R⁴ is bonded to the ring nitrogen of Formula I through anunsaturated carbon bond and R⁴ is optionally substituted with one ormore groups independently selected from oxo (provided it is not on anitrogen, oxygen or an unsaturated carbon), halogen, cyano, nitro,trifluoromethyl, difluoromethyl, fluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR¹⁰R¹¹, —NR¹⁰SO₂R¹³, —SO₂NR¹⁰R¹¹, —C(═O)R¹⁰,—C(O)OR¹⁰, —OC(═O)R¹⁰, —NR¹⁰C(═O)OR¹³, —NR¹⁰C(═O)R¹¹, —C(═O)NR¹⁰R¹¹,—SR¹⁰, —S(O)R¹³, —SO₂R¹³, SO₂NHC(═O)R¹⁰, —NR¹⁰C(═O)NR¹¹(OR¹²),—NR¹⁰C(═O)NR¹¹R¹², —NR¹⁰C(NCN)NR¹¹R¹²—NR¹⁰C(H)NR¹¹R¹²,—NR¹⁰C(R¹³)NR¹¹R¹², —OR¹⁰, alkyl, cycloalkyl, alkenyl, alkynyl,heteroalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, —OP(═O)(OR¹⁰)₂, an amino acid residue, a dipeptideand a tripeptide, wherein said alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl are optionally substituted with one or more groupsindependently selected from oxo (with the proviso that it is not on saidaryl or heteroaryl portions), halogen, cyano, nitro, hydroxy, —OR¹⁰,NR¹⁰R¹¹, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR¹⁰SO₂R¹³, —SO₂NR¹⁰R¹¹, —C(═O)R¹⁰, —C(═O)OR¹⁰, —OC(═O)R¹⁰,—NR¹⁰C(═O)OR¹¹, —NR¹⁰C(═O)R¹¹, —C(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹³, —SO₂R¹³,SO₂NHC(═O)R¹⁰, —NR¹⁰C(═O)NR¹¹R¹², —NR¹⁰C(NCN)NR¹¹R¹², alkyl, cycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl;

R¹⁰, R¹¹ and R¹² independently are selected from hydrogen, alkyl,trifluoromethyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocyclyl and arylalkyl, wherein said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, heterocyclyl and arylalkyl are optionallysubstituted with one or more groups independently selected from oxo(with the proviso that it is not on said aryl or heteroaryl portions),halogen, cyano, nitro, OR¹⁴, —NR¹⁴R¹⁵, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;

R¹³ is alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl orarylalkyl, wherein said alkyl, alkenyl, cycloalkyl, aryl, heteroaryl,heterocyclyl and arylalkyl are optionally substituted with one to threegroups independently selected from oxo (with the proviso that it is noton said aryl or heteroaryl portions), halogen, cyano, nitro, OR¹⁴,—NR¹⁴R¹⁵, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl,

or any two of R¹⁰, R¹¹, R¹² and R¹³ together with the atoms to whichthey are attached form a 4 to 10 membered heteroaryl or heterocyclicring, wherein said heteroaryl and heterocyclic rings are optionallysubstituted with one to three groups independently selected from oxo(with the proviso that it is not on said heteroaryl ring), halogen,cyano, nitro, OR¹⁴, —NR¹⁴R¹⁵, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;

R¹⁴ and R¹⁵ are independently selected from hydrogen, alkyl, alkenyl,lower alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl and arylalkyl,

or R¹⁴ and R¹⁵ together with the atoms to which they are attached form asaturated, partially unsaturated or fully unsaturated 5-6 memberedheterocyclyl;

R¹⁷, R²² and R²³ are independently H or alkyl;

R¹⁸ is H, OH, O-alkyl, CN, C(═O)NH₂, C(═O)NH(alkyl), C(═O)N(alkyl)₂,C(═O)alkyl, or alkyl optionally substituted with one or more groupsindependently selected from halogen, CN, OH, O-alkyl, NH₂, NH-alkyl,N(alkyl)₂ and aryl;

R¹⁹ is H or alkyl optionally substituted with one or more groupsindependently selected from halogen, NO₂, halogen, CN, OH, O-alkyl, NH₂,NH-alkyl, N(alkyl)₂ and aryl; and

R²⁰ and R²¹ are independently H, C(═O)alkyl, or alkyl optionallysubstituted with one or more groups independently selected from halogen,CN, OH, O-alkyl, NH₂, NH-alkyl, N(alkyl)₂ and aryl,

or R²⁰ and R²¹ together with the atoms to which they are attached form a5-6 membered unsaturated or partially unsaturated heterocyclic ring;

or R¹⁸ and R²⁰ together with the atoms to which they are attached form a5-6 membered partially unsaturated or fully unsaturated heterocyclicring;

or R¹⁷ and R²⁰ together with the atoms to which they are attached form a5-6 membered unsaturated or partially unsaturated heterocyclic ring.

In another embodiment there is provided a compound of Formula I

and metabolites, solvates, tautomers, and pharmaceutically acceptablesalts and prodrugs thereof, wherein:

W is S(O)_(m);

m is 0, 1 or 2;

R¹ is H, alkyl, cycloalkyl, heteroalkyl, alkenyl or alkynyl, whereinsaid alkyl, cycloalkyl, heteroalkyl, alkenyl and alkynyl are optionallysubstituted with one or more groups independently selected from oxo,halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —OR¹⁰, —NR¹⁰R¹¹, NR¹⁰SO₂R¹³, —C(O)R¹⁰,—OC(═O)R¹⁰, —C(═O)OR¹⁰, —C(═O)NR¹⁰R¹¹, —NR¹⁰C(O)OR¹³, —NR¹⁰C(O)R¹¹,—SR¹⁰, —S(O)R¹³, —SO₂R¹³, —SO₂NHC(═O)R¹⁰, —NR¹⁰C(═O)NR¹¹R¹²,—NR¹⁰C(NCN)NR¹¹R¹², alkyl, cycloalkyl, alkenyl, alkynyl, aryl,arylalkyl, heterocyclyl, heterocyclylalkyl, —OP(═O)(OR¹⁰)₂, an aminoacid residue, a dipeptide and a tripeptide, with the proviso that saidalkyl does not terminate with a —C(═O)OR¹⁰ group;

Ar¹ and Ar² are independently phenyl or a 5 or 6 membered heteroarylring having 1 to 3 heteroatoms independently selected from N, O or S,wherein said heteroaryl is a carbon radical and wherein said phenyl andheteroaryl are optionally substituted with one or more groupsindependently selected from halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —OR¹⁰, —NR¹⁰R¹¹, —NR¹⁰SO₂R¹³,SO₂NR¹⁰R¹¹, —C(═O)R¹⁰, —C(O)OR¹⁰, —OC(═O)R¹⁰, —NR¹⁰C(═O)OR¹³,—NR¹⁰C(═O)R¹¹, —C(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹³, —SO₂R¹³, —SO₂NHC(═O)R¹⁰,—NR¹⁰C(═O)NR¹¹R¹², —NR¹⁰C(NCN)NR¹¹R¹², alkyl, cycloalkyl, alkenyl,alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl;

R⁴ is

wherein a dashed line represents an optional double bond;

D¹ is N, NR⁶, CR⁵, CR⁵R^(5a), or C(═O);

D² is CR⁵, CR⁵R^(5a), N or NR⁶;

D³ is S, O, N, NR⁶ or CR⁵R^(5a);

E is O, S or NR⁶;

A is a saturated, partially unsaturated, or fully unsaturated 5-8carbocyclic ring or heterocyclic ring having 1 to 3 heteroatomsindependently selected from N, O or S, wherein said carbocyclic andheterocyclic rings are optionally substituted with one or more groupsindependently selected from halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, oxo, —OR¹⁰, —NR¹⁰R¹¹,—NR¹⁰SO₂R¹³, SO₂NR¹⁰R¹¹, —C(═O)R¹⁰, —C(═O)OR¹⁰, —OC(═O)R¹⁰,—NR¹⁰C(═O)OR¹³, —NR¹⁰C(═O)R¹¹, —C(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹³, —SO₂R¹³,—SO₂NHC(═O)R¹⁰—NR¹⁰C(═O)NR¹¹R¹², —NR¹⁰C(NCN)NR¹¹R¹², alkyl, cycloalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl, wherein said alkyl, cycloalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl are optionally substituted with oneor more groups independently selected from oxo (with the proviso that itis not on said aryl or heteroaryl portions), halogen, cyano, nitro,hydroxy, —OR¹⁰, NR¹⁰R¹¹, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR¹⁰SO₂R¹³, —SO₂NR¹⁰R¹¹, —C(═O)R¹⁰,—C(═O)OR¹⁰, —OC(═O)R¹⁰, —NR¹⁰C(═O)OR¹¹, —NR¹⁰C(═O)R¹¹, —C(═O)NR¹⁰R¹¹,—SR¹⁰, —S(O)R¹³, —SO₂R¹³, SO₂NHC(═O)R¹⁰, —NR¹⁰C(═O)NR¹¹R¹²,—NR¹⁰C(NCN)NR¹¹R¹², alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl;

each R⁵ and R^(5a) is independently selected from H, halogen, cyano,nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR¹⁰R¹¹, —NR¹⁰SO₂R¹³, —SO₂NR¹⁰R¹¹, —C(═O)R¹⁰, —C(═O)OR¹⁰, —OC(═O)R¹⁰,—NR¹⁰C(═O)OR¹³, —NR¹⁰C(═O)R¹¹, —C(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹³, —SO₂R¹³,—SO₂NHC(═O)R¹⁰, —NR¹⁰C(═O)NR¹¹R¹², —NR¹⁰C(NCN)NR¹¹R¹², —OR¹⁰, alkyl,cycloalkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl, wherein said alkyl,cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl are optionallysubstituted with one or more groups independently selected from oxo(with the proviso that it is not on said aryl or heteroaryl portions),halogen, cyano, nitro, hydroxy, —OR¹⁰, NR¹⁰R¹¹, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR¹⁰SO₂R¹³, —SO₂NR¹⁰R¹¹,—C(═O)R¹⁰, —C(═O)OR¹⁰, —OC(═O)R¹⁰, —NR¹⁰C(═O)OR¹¹, —NR¹⁰C(═O)R¹¹,—C(═O)NR¹⁰R¹¹, —SR¹¹, —S(O)R¹³, —SO₂R¹³, SO₂NHC(═O)R¹⁰,—NR¹⁰C(═O)NR¹¹R¹², —NR¹⁰C(NCN)NR¹¹R¹², alkyl, cycloalkyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl;

R⁶ is H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl orheterocyclyl, wherein said alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl and heterocyclyl are optionally substituted with one or moregroups independently selected from oxo, halogen, cyano, nitro, hydroxy,—OR¹⁰, NR¹⁰R¹¹, trifluoromethyl, difluoromethoxy, trifluoromethoxy,azido, —NR¹⁰SO₂R¹³, —SO₂NR¹⁰R¹¹, —C(═O)R¹⁰, —C(═O)OR¹¹, —OC(═O)R¹¹,—NR¹⁰C(═O)OR¹¹, —NR¹⁰C(═O)R¹¹, —C(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹³, —SO₂R¹³,—SO₂NHC(═O)R¹⁰, —NR¹⁰C(═O)NR¹¹R¹², —NR¹⁰C(NCN)NR¹¹R¹², alkyl,cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyland heterocyclylalkyl;

R¹⁰, R¹¹ and R¹² independently are selected from hydrogen, alkyl,trifluoromethyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocyclyl and arylalkyl, wherein said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, heterocyclyl and arylalkyl are optionallysubstituted with one or more groups independently selected from oxo(with the proviso that it is not on said aryl portions), halogen, cyano,nitro, OR¹⁴, —NR¹⁴R¹⁵, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl;

R¹³ is alkyl, alkenyl, cycloalkyl, aryl or arylalkyl, wherein saidalkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl and arylalkylare optionally substituted with one to three groups independentlyselected from oxo (with the proviso that it is not on said arylportions), halogen, cyano, nitro, OR¹⁴, NR¹⁴R¹⁵, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, alkyl, cycloalkyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl;

or any two of R¹⁰, R¹¹, R¹² and R¹³ together with the atoms to whichthey are attached form a 4 to 10 membered heteroaryl or heterocyclicring, wherein said heteroaryl and heterocyclic rings are optionallysubstituted with one to three groups independently selected from oxo(with the proviso that it is not on said heteroaryl ring), halogen,cyano, nitro, OR¹⁴, NR¹⁴R¹⁵, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl; and

R¹⁴ and R¹⁵ are independently selected from hydrogen, alkyl, alkenyl,lower alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl and arylalkyl.

In certain embodiments of Formula I, W is S.

According to another embodiment, R¹ is alkyl or heteroalkyl, whereinsaid alkyl and heteroalkyl are optionally substituted with one or moregroups independently selected from —OR¹⁰, —NR¹⁰R¹¹, —OP(═O)(OR¹⁰)₂, anamino acid residue, a dipeptide and a tripeptide. In another embodiment,there is provided a compound of Formula I, wherein R¹ is alkyloptionally substituted with NR¹⁰C(═O)(CH₂)₀₋₂R¹¹, NR¹⁰SO₂R¹³,heterocyclyl, or R¹ is a heterocyclyl.

Exemplary embodiments include compounds of Formula I wherein R¹ is(CH₂)₂—OH, (CH₂)₃—OH, (CH₂)—NH₂, (CH₂)₂—NH₂, (CH₂)₃—NH₂,(CH₂)₃—NHCH(CH₃)₂, (CH₂)₂—NHMe, (CH₂)₂—NMe₂, (CH₂)₃—NMe₂, (CH₂)₃—NHMe,(CH₂)₃NHC(═O)Me, (CH₂)₃NHC(═O)CH(CH₃)₂, (CH₂)₃NHC(═O)CH₂CH₂NMe₂,(CH₂)₃NHSO₂Me, (CH₂)₃-(pyrrolidin-1-yl), (CH₂)₃-(piperidin-1-yl),(CH₂)₃-(4-methylpiperidin-1-yl), (CH₂)₃-(morpholin-4-yl),(CH₂)₂-(pyrrolidin-2-yl), (CH₂)₃NH(C═O)CH(Me)NH(C═O)CH(Me)NH₂,(CH₂)₃—OPO₃H₂, CH₂—O—CH₂OMe or piperidin-4-yl.

In particular embodiments, there is provided a compound of Formula Iwherein R¹ is —(CH₂)₃NH₂.

In certain embodiments, R¹ is Z—NR¹⁷—C(═NR¹⁸)R¹⁹,Z—NR¹⁷—C(═NR¹⁸)NR²⁰R²¹Z—C(═NR¹⁸)NR²⁰R²¹, Z—O—NR¹⁷C(═NR¹)NR)NR²⁰R²¹,Z—O—NR¹⁷—C(═NR)R²⁰, Z—NR²²—NR²³—C(═NR¹⁸)R¹⁹, orZ—NR²²—NR²³—C(═NR¹⁸)NR²⁰R²¹.

In certain embodiments, there is provided a compound of Formula Iwherein Ar¹ is phenyl optionally substituted with one or more groupsindependently selected from halogen, alkyl, —OR¹⁰ or —NR¹⁰R¹¹; or Ar¹ isa heteroaryl selected from thiophenyl or pyridyl, wherein said pyridylis optionally substituted independently with one or more halogens.

Exemplary embodiments of such Ar¹ groups include phenyl,2,4-difluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 2-chlorophenyl,3-chlorophenyl, 2,5-dichlorophenyl, 2,3-dichlorophenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-chloro-5-fluorophenyl,2-fluoro-5-chlorophenyl, 2-chloro-5-methylphenyl,2-trifluoromethyl-5-fluorophenyl, 2-fluoro-5-methoxyphenyl,thiophen-2-yl, thiophen-3-yl, 5-chlorothiophen-2-yl, 2-pyridyl,3-pyridyl, 4-chloropyridin-3-yl, 3-chloropyridin-2-yl,4-fluoropyridin-3-yl, or 3,6-difluoropyridin-2-yl.

In particular embodiments, Ar¹ is 2,4-difluorophenyl.

According to yet another embodiment, Ar² is an optionally substitutedphenyl group. In certain embodiments, Ar² is substituted with one ormore halogen groups. In a particular embodiment, Ar² is2,4-difluorophenyl, 2,5-difluorophenyl, or 3-fluorophenyl. In otherembodiments, Ar² is phenyl, 2-chlorophenyl, 4-chlorophenyl,4-fluorophenyl, 4-bromophenyl or 3,4-dichlorophenyl.

In other embodiments, there is provided a compound of Formula I whereinAr² is phenyl optionally substituted with one or more groupsindependently selected from OR¹⁰, NR¹⁰R¹¹, CN, NO₂, —OP(═O)(OR¹⁰)₂,C(═O)OR¹⁰, or Ar² is a heteroaryl selected from pyridyl, thiophenyloptionally substituted with alkyl, imidazolyl, and pyrazolyl optionallysubstituted with NR¹⁰R¹¹. For example, in certain embodiments, Ar² is2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl,3,5-dimethylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-t-butylphenyl,3-nitrophenyl, 3-hydroxyphenyl, 3-(OPO₃H₂)-phenyl, 3-aminophenyl,3-carboxyphenyl, 3-cyanophenyl, 2-pyridyl, 3-pyridyl,5-methylthiophen-2-yl, 2-methylthiazol-4-yl, 2-(1H-imidazol-2-yl),2-(1H-imidazol-4-yl) or 3-amino-1H-pyrazol-5-yl.

In particular embodiments, Ar² is phenyl.

In certain embodiments, there is provided a compound of Formula I,wherein R⁴ is selected from:

wherein:

a dashed line represents an optional double bond;

D¹ is N, NR⁶, O, CR⁵, CR⁵R^(5a), or C(═O);

D² is CR⁵, CR⁵R^(5a), N, NR⁶, O, S or C(═O), wherein only one of D¹ andD² is C(═O);

D³ is S, O, N, NR⁶, CR⁵ or CR⁵R^(5a);

D⁴ and D⁵ are independently N, NR⁶, S or O;

E is O, S or NR⁶

Y¹ and Y² are CH₂, C═O or SO₂ wherein:

Y³ is CH₂ or NR⁶;

X¹ is O or S;

X² is C═O or SO₂;

X³ and X⁴ are independently CH₂ or CMe₂ when the bond represented by---- is absent or X³ and X⁴ are independently CH or CMe when the bondrepresented by ---- is present;

X⁵ is S, O, NR⁶, SO, SO₂, or CR⁵CR^(5a)

Z¹, Z², and Z³ are independently N or CR⁵, wherein 1 or 2 of Z¹, Z² andZ³ is N;

one of Z⁴ and Z⁵ is N and the other is CR⁵;

A is a saturated, partially unsaturated, or fully unsaturated 5-8carbocyclic ring or heterocyclic ring having 1 to 3 ring heteroatomsindependently selected from N, O, S, or SO₂, wherein said carbocyclicand heterocyclic rings are optionally substituted independently with oneor more R⁷ groups;

G is a saturated, or partially unsaturated, or fully unsaturated 5membered heterocyclic ring having 1-3 ring heteroatoms independentlyselected from N S, O, SO and SO₂, wherein G is optionally substitutedindependently with one or more R⁷ groups;

K is a benzene ring or a saturated or partially unsaturated 5-6 memberedheterocyclic ring having 1-3 ring heteroatoms independently selectedfrom N S, O, SO and SO₂, wherein K is optionally substituted with one ormore R⁷ groups;

each R⁵ and R^(5a) is independently selected from H, halogen, cyano,nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR¹⁰R¹¹, —NR¹⁰SO₂R¹³, —SO₂NR¹⁰R¹¹, —C(═O)R¹⁰, —C(O)OR¹⁰, —OC(═O)R¹⁰,—NR¹⁰C(═O)OR¹³, —NR¹⁰C(═O)R¹¹, —C(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹³, —SO₂R¹³,SO₂NHC(═O)R¹⁰, —NR¹⁰C(═O)NR¹¹(OR¹²), —NRIC(═O)NR¹¹R¹²,—NR¹⁰C(NCN)NR¹¹R¹², —OR¹⁰, alkyl, cycloalkyl, alkenyl, alkynyl,heteroalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyland heterocyclylalkyl, wherein said alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl are optionally substituted with one or more groupsindependently selected from oxo (with the proviso that it is not on saidaryl or heteroaryl portions), halogen, cyano, nitro, hydroxy, —OR¹⁰,NR¹⁰R¹¹, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR¹⁰SO₂R¹³, —SO₂NR¹⁰R¹¹, —C(═O)R¹⁰, —C(═O)OR¹⁰, —OC(═O)R¹,—NR¹⁰C(═O)OR¹¹, —NR¹⁰C(═O)R¹¹, —C(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹³, —SO₂R¹³,—SO₂NHC(═O)R¹⁰, —NR¹⁰C(═O)NR¹¹R¹², —NR¹⁰C(NCN)NR¹¹R¹², alkyl,cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl,and heterocyclylalkyl;

R⁶ is H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl orheterocyclyl, wherein said alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl and heterocyclyl are optionally substituted with one or moregroups independently selected from oxo, halogen, cyano, nitro, hydroxy,—OR¹⁰, NR¹⁰R¹¹, trifluoromethyl, difluoromethoxy, trifluoromethoxy,azido, —NR¹⁰SO₂R¹³, —SO₂NR¹⁰R¹¹, —C(═O)R¹⁰, —C(═O)OR¹⁰, —OC(═O)R¹⁰,—NR¹⁰C(═O)OR¹¹, —NR¹⁰C(═O)R¹¹, —C(═O)NRoR¹¹, —SR¹⁰, —S(O)R¹³, —SO₂R¹³,SO₂NHC(═O)R¹⁰, —NR¹⁰C(═O)NR¹¹R¹², —NR¹⁰C(NCN)NR¹¹R¹², alkyl, cycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl;

R^(6a) is independently H or alkyl;

R⁷ is halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, oxo (provided it is not on a nitrogen, oxygenor unsaturated carbon), —OR¹⁰, —NR¹⁰R¹¹, —NR¹⁰SO₂R¹³SO₂NR¹⁰R¹¹,—C(═O)R¹⁰, —C(═O)OR¹⁰, —OC(═O)R¹¹, —NR¹⁰C(═O)OR¹³, —NR¹⁰C(═O)R¹¹,—C(═O)NR¹⁰R¹¹, —C(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹³—SO₂R¹³,—SO₂NHC(═O)R¹⁰—NR¹⁰C(═O)NR¹¹R¹², C(═NH)NH(CN), —NR¹⁰C(NCN)NR¹¹R¹²,alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl, wherein said alkyl,cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl are optionallysubstituted with one or more groups independently selected from oxo(with the proviso that it is not on said aryl or heteroaryl portions),halogen, cyano, nitro, hydroxy, —OR¹⁰, NR¹⁰R¹¹, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR¹⁰SO₂R¹³, —SO₂NR¹⁰R¹¹,—C(═O)R¹⁰, —C(═O)OR10, —OC(═O)R¹⁰, —NR¹⁰C(═O)OR¹¹, —NR¹⁰C(═O)R¹¹,—C(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹³, —SO₂R¹³, SO₂NHC(═O)R¹¹,—NR¹⁰C(═O)NR¹¹R¹², NR¹⁰C(═O)NR¹⁰R¹², —NR¹⁰C(NCN)NR¹¹R¹², OPO₃H, alkyl,cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyland heterocyclylalkyl;

RC is H or Me; and

n is 0, 1 or 2.

Exemplary embodiments of R⁴ include, but are not limited to,2-thiazolyl, fused thiazolyl ring systems, 2-oxazolyl, fused oxazolylring systems, 2-imidazolyl, oxadiazolyl, thiadiazolyl, 4,5(H)-thiazolyl,4-triazolyl, 4,5(H)-oxazolyl, fused 4,5(H)-thiazolyl ring systems,dihydropyrrol-2-on-yl, and substituted forms thereof, and shown as:

wherein the asterisk indicates the point of attachment, “A” is asdefined above, and each R⁵ and R^(5a) is independent of every other R⁵and R^(5a)

More specific embodiments of R⁴ include

Further exemplary embodiments include compounds of Formula I wherein R⁴is selected from

In certain embodiments, there is provided a compound of Formula Iwherein R⁴ is selected from the structures

wherein R⁵, R^(5a) and R⁶ are as defined for Formula I. In certainembodiments, R⁵ and R^(5a) are independently H, halogen, alkyl, aryl, orNR¹⁰R¹¹, wherein said alkyl and aryl are optionally substituted with oneor more groups independently selected from halogen and —C(═O)OR¹⁰.

In certain embodiments, there is provided a compound of Formula Iwherein R⁴ is

and A is a saturated or partially unsaturated heterocyclic ring having aring nitrogen, wherein 1-2 carbon atoms of said heterocyclic ring areoptionally substituted with a group independently selected from halogenor alkyl optionally substituted with one or more halogen, and thenitrogen of said heterocyclic ring is optionally substituted withC(═O)NR¹⁰R¹¹, C(═O)N(R¹⁰)OR¹¹, C(═NH)CH—CN, or alkyl optionallysubstituted with one or more groups independently selected from OR¹⁰,OPO₃H₂, NR¹⁰R¹¹ and heterocyclyl.

Exemplary embodiments include compounds of Formula I wherein R⁴ isselected from the structures:

In certain embodiments, there is provided a compound of Formula Iwherein R⁴ is

and A is a saturated or partially unsaturated 5 membered heterocyclicring, wherein said heterocyclic ring is optionally substituted with oneor more groups independently selected from halogen, alkyl, SO₂Me, andoxo.

Exemplary embodiments include compounds of Formula I wherein R⁴ isselected from the structures:

In certain embodiments, there is provided a compound of Formula Iwherein R⁴ is

and A is a benzene ring, wherein the benzene ring is optionallysubstituted with one or more groups independently selected from halogen,CN, NO₂, C(═O)NR¹⁰R¹¹, NR¹⁰C(═O)NR¹¹R¹², heteroaryl optionallysubstituted with alkyl, and alkyl optionally substituted with OR¹⁰,NR¹⁰R¹¹ or NR¹⁰C(═O)N(R¹¹)OR¹².

Examples of halogen substituents include F and Cl. Examples ofC(═O)NR¹⁰R¹¹ substituents include C(═O)NH₂, C(═O)NHCH₃, andC(═O)N(CH₃)₂. Examples of NR¹⁰C(═O)NR¹¹R¹² substituents includeNHC(═O)NH₂, NHC(═O)NHCH₃, and NHC(═O)N(CH₃)₂. Examples of heteroarylsubstituents optionally substituted with alkyl include1,2,4-triazol-1-yl and 3-methyl-1,2,4-triazol-1-yl. Examples of alkylsubstituents optionally substituted with OR¹⁰, NR¹⁰R¹¹ orNR¹⁰C(═O)N(R¹¹)OR¹² include CH₂OH, CH₂CH₂OH, CH₂CH₃, CH₂CH₂OCH₃,CH₂OCH₂CH₃, CH₂CH₂OCH₂CH₃, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂CH₂NH₂,CH₂CH₂NHCH₃, CH₂CH₂N(CH₃), CH₂NHC(═O)NHOH, and CH₂NHC(═O)NHOCH₃.

Exemplary embodiments include compounds of Formula I wherein R⁴ isselected from the structures:

In certain embodiments, there is provided a compound of Formula Iwherein R⁴ is selected from the structures:

For example, in certain embodiments there is provided a compound ofFormula I wherein R⁴ is

wherein R⁶ and R^(6a) are independently selected from H and alkyl. Incertain embodiments, said alkyl is selected from methyl, ethyl, propyl,isopropyl, butyl, and the like.

Exemplary embodiments include compounds of Formula I wherein R⁴ isselected from the structures:

In certain embodiments there is provided a compound of Formula I whereinR⁴ is

wherein A is a partially unsaturated or fully unsaturated 5-memberedheterocyclic ring, wherein said heterocyclic ring is optionallysubstituted independently with one or more alkyl groups, such as, butnot limited to, methyl, ethyl, propyl, isopropyl, butyl, and the like.

Exemplary embodiments include compounds of Formula I wherein R⁴ isselected from the structures:

In certain embodiments there is provided a compound of Formula I wherein

Exemplary embodiments include compounds of Formula I wherein R⁴ isselected from the structures:

In certain embodiments there is provided a compound of Formula I whereinR⁴ is

Exemplary embodiments include compounds of Formula I wherein R⁴ isselected from the structures:

In certain embodiments there is provided a compound of Formula I whereinR⁴ is

wherein K is optionally substituted independently with one or more alkylgroups, such as, but not limited to, methyl, ethyl, propyl, isopropyl,butyl, and the like.

Exemplary embodiments include compounds of Formula I wherein R⁴ isselected from the structures:

wherein R⁶ is alkyl. Examples of alkyl groups include, but are notlimited to, methyl, ethyl, propyl, isopropyl, butyl, and the like.

In certain embodiments there is provided a compound of Formula I whereinR⁴ is

wherein G is optionally substituted independently with one or more alkylgroups, such as, but not limited to, methyl, ethyl, propyl, isopropyl,butyl, and the like.

Exemplary embodiments include compounds of Formula I wherein R⁴ isselected from the structures:

In certain embodiments there is provided a compound of Formula I whereinR⁴ is

Exemplary embodiments include compounds of Formula I wherein R⁴ isselected from the structures:

In certain embodiments there is provided a compound of Formula I whereinR⁴ is

wherein n is 0 or 1, and each R⁵ is independently NO₂, C(═O)NR¹⁰R¹¹,NR¹⁰C(═O)N(R¹¹)OR¹², halogen, CN, or alkyl optionally substituted withone or more groups independently selected from halogen, OR¹⁰ andNR¹⁰R¹¹. Examples of C(═O)NR¹⁰R¹¹ substituents include C(═O)NH₂,C(═O)NHCH₃, and C(═O)N(CH₃)₂. Examples of halogen substituents include Fand Cl. Examples of alkyl substituents optionally substituted withhalogen, OR¹⁰, or NR¹⁰R¹¹ include CH₂F, CHF₂, CF₃, CH₂CH₂F, CH₂CHF₂,CH₂CF₃, CH₂Cl, CH₂Br, CH₂OH, CH₂CH₂OH, CH₂OCH₃, CH₂CH₂OCH₃, CH₂OCH₂CH₃,CH₂CH₂OCH₂CH₃, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂CH₂NH₂, CH₂CH₂NHCH₃, andCH₂CH₂N(CH₃)

Exemplary embodiments include compounds of Formula I wherein R⁴ isselected from the structures:

In certain embodiments there is provided a compound of Formula I whereinR⁴ is selected from

wherein n is 0 or 1, and each R⁵ is independently NO₂, C(═O)NR¹⁰R¹¹,NR¹⁰C(═O)N(R¹¹)OR¹², halogen, CN, or alky optionally substituted withone or more groups independently selected from halogen, OR¹⁰ andNR¹⁰R¹¹.

Exemplary embodiments include compounds of Formula I wherein R⁴ isselected from the structures:

In certain embodiments there is provided a compound of Formula I whereinR⁴ is

Exemplary embodiments include compounds of Formula I wherein R⁴ isselected from the structures:

In certain embodiments there is provided a compound of Formula I whereinR⁴ is

Exemplary embodiments include compounds of Formula I wherein R⁴ isselected from the structures:

Certain compounds of Formula I can exist as two or more tautomericforms. A “tautomer” is one of two or more structural isomers that existin equilibrium and are readily converted from one isomeric form toanother, such as structures formed by the movement of a hydrogen fromone site to another within the same molecule. Other tautomeric forms ofthe compounds may interchange, for example, viaenolization/de-enolization and the like. Accordingly, the presentinvention includes the preparation of all tautomeric forms of compoundsof Formula I.

The term “alkyl” as used herein refers to a saturated linear orbranched-chain monovalent hydrocarbon radical having one to ten carbonatoms, wherein the alkyl radical may be optionally substitutedindependently with one or more substituents described herein. Examplesof alkyl groups include, but are not limited to, methyl, ethyl,n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, tert-pentyl, hexyl, 2-hexyl, 3-hexyl,3-methylpentyl, heptyl, octyl and the like.

Additional examples of alkyl groups include, but are not limited to,2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu,t-butyl, —C(CH₃)₃), 1-pentyl(n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl(—CH(CH₃)CH₂CH₂CH₃), 3-pentyl (—CH(CH₂CH₃)₂), 2-methyl-2-butyl(—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl(—CH₂CH₂CH(CH₃)₂), 2-methyl-i-butyl (—CH₂CH(CH₃)CH₂CH₃),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, and the like.

As used herein, an alkyl optionally substituted with one or more halogengroups includes, but is not limited to, CH₂F, CHF₂, CF₃, CH₂CH₂F,CH₂CHF₂, CH₂CF₃, CH₂CL, CH₂Br, and the like.

As used herein, an alkyl optionally substituted with one or more—C(═O)OR¹⁰ includes, but is not limited to, CH₂CO₂CH₃, CH₂CO₂CH₂CH₃,CH₂CH₂CO₂CH₃, CH₂CH₂CO₂CH₂CH₃, and the like.

As used herein, an alkyl optionally substituted with one or more OR¹⁰includes CH₂OH, CH₂CH₂OH, CH₂CH₂CH₂OH, CH₂CH₂CH(OH)CH₃, CH₂C(OH)(CH₃)₂,CH₂—O—CH₂OMe, and the like.

As used herein, an alkyl optionally substituted with one or more OPO₃H₂includes CH₂OPO₃H₂, CH₂CH₂OPO₃H₂, CH₂CH₂CH₂OPO₃H₂, and the like.

As used herein, an alkyl optionally substituted with one or more NR¹⁰R¹¹includes CH₂NH₂, CH₂CH₂NH₂, CH₂CH₂CH₂NH₂, CH₂NHMe, CH₂CH₂NHMe,CH₂CH₂CH₂NHMe, CH₂NMe₂, CH₂CH₂NMe₂, CH₂CH₂CH₂NMe₂, and the like.

As used herein, an alkyl optionally substituted with an amino acidresidue includes an alkyl group such as CH₂, CH₂CH₂, or CH₂CH₂CH₂substituted with any of the natural amino acids, wherein the amino acidis of the D or L configuration. Examples include, but are not limitedto, (CH₂)₃NH(C═O)CH(Me)NH(C═O)CH(Me)NH₂, (CH₂)₃NHCH(CH₃)(C═O)NH₂, andthe like.

As used herein, an alkyl optionally substituted with a dipeptideincludes CH₂-alanine-alanine, CH₂CH₂-alanine-alanine,CH₂CH₂CH₂-alanine-alanine, and the like, wherein each amino acid residueof the peptide is of the D or L configuration.

As used herein, an alkyl optionally substituted with a tripeptideincludes an alkyl such as CH₂, CH₂CH₂, or CH₂CH₂CH₂ substituted with atripeptide such as, but not limited to, alanine-alanine-alanine,valine-alanine-valine, alanine-valine-valine, and the like, wherein eachamino acid residue of the peptide is of the D or L configuration.

As used herein, an alkyl optionally substituted with one or moreheterocyclyl includes (CH₂)₃-(pyrrolidin-1-yl), (CH₂)₃-(piperidin-1-yl),(CH₂)₃-(4-methylpiperidin-1-yl), (CH₂)₃-(morpholin-4-yl),(CH₂)₄-(morpholin-4-yl), (CH₂)₂-(pyrrolidin-2-yl), and the like.

As used herein, an alkyl optionally substituted with one or moreNR¹⁰C(═O)N(R¹¹)OR¹² includes CH₂NHC(═O)N(OMe)Me and the like.

As used herein, an alkyl optionally substituted with one or moreNR¹⁰C(═O)(CH₂)₀₋₂R¹¹ includes (CH₂)₃NHC(═O)Me, (CH₂)₃NHC(═O)CH(CH₃)₂,(CH₂)₃NHC(═O)CH₂CH₂NMe₂ and the like.

As used herein, an alkyl optionally substituted with one or moreNR¹⁰SO₂R¹³ includes (CH₂)₃NHSO₂Me, (CH₂)₂NHSO₂Me and the like.

The term “alkylene” as used herein refers to a linear or branchedsaturated divalent hydrocarbon radical of one to twelve carbon atoms,wherein the alkylene radical may be optionally substituted independentlywith one or more substituents described herein. Examples of alkylenegroups include, but are not limited to, methylene, ethylene, propylene,2-methylpropylene, pentylene and the like.

The term “alkenyl” refers to a linear or branched-chain monovalenthydrocarbon radical having two to ten carbon atoms and at least onedouble bond, and includes, but is not limited to, ethenyl, propenyl,1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl and the like, wherein thealkenyl radical may be optionally substituted independently with one ormore substituents described herein, and includes radicals having “cis”and “trans” orientations, or alternatively, “E” and “Z” orientations.

The term “alkenylene” refers to a linear or branched divalenthydrocarbon radical of two to twelve carbons containing at least onedouble bond, wherein the alkenylene radical may be optionallysubstituted independently with one or more substituents describedherein. Examples include, but are not limited to, ethenylene,propenylene and the like.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical of two to twelve carbon atoms containing at least one triplebond. Examples include, but are not limited to, ethynyl, propynyl,butynyl, pentyn-2-yl and the like, wherein the alkynyl radical may beoptionally substituted independently with one or more substituentsdescribed herein.

The term “alkynylene” refers to a linear or branched divalenthydrocarbon radical of two to twelve carbons containing at least onetriple bond, wherein the alkynylene radical may be optionallysubstituted independently with one or more substituents describedherein.

The terms “carbocycle,” “carbocyclyl,” “cycloalkyl,” and “carbocyclicring” are used interchangeably herein and refer to a saturated orpartially unsaturated cyclic monovalent hydrocarbon radical having fromthree to ten carbon atoms. The term “cycloalkyl” includes monocyclic andpolycyclic (e.g., bicyclic and tricyclic) cycloalkyl structures, whereinthe polycyclic structures optionally include a saturated or partiallyunsaturated cycloalkyl fused to a saturated or partially unsaturatedcycloalkyl or heterocycloalkyl ring or an aryl or heteroaryl ring.Examples of cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and thelike. The cycloalkyl may be optionally substituted independently at oneor more substitutable positions with one or more substituents describedherein. Such cycloalkyl groups may be optionally substituted with, forexample, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro,amino, mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl,mono(C₁-C₆)alkylamino(C₁-C₆)alkyl or di(C₁-C₆)alkylamino(C₁-C₆)alkyl.Bicyclic carbocycles include those having 7 to 12 ring atoms arranged,for example, as a bicyclo[4,5], [5,5], [5,6] or [6,6] system, or asbridged systems such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, andbicyclo[3.2.2]nonane.

The term “heteroalkyl” refers to saturated linear or branched-chainmonovalent hydrocarbon radical of one to twelve carbon atoms, wherein atleast one of the carbon atoms is replaced with a heteroatom selectedfrom N, O, or S, and wherein the radical may be a carbon radical orheteroatom radical (i.e., the heteroatom may appear in the middle or atthe end of the radical). The heteroalkyl radical may be optionallysubstituted independently with one or more substituents describedherein. The term “heteroalkyl” encompasses alkoxy and heteroalkoxyradicals. For example, heteroalkyls include methoxy (OCH₃),ethoxy(OCH₂CH₃) and the like. Examples further include heteroalkylssubstituted with one or more halogen. Examples include, but are notlimited to, fluoromethoxy(OCH₂F), difluoromethoxy(OCHF₂),trifluoromethoxy(OCF₃), and the like. Accordingly, a OR¹⁰ substituent asdefined herein can include, but is not limited to, OCH₃, OCH₂CH₃, OCH₂F,(OCHF₂), and (OCF₃).

The term “heteroalkylene” refers to a linear or branched saturateddivalent hydrocarbon radical of one to twelve carbon atoms, wherein atleast one of the carbon atoms is replaced with a heteroatom selectedfrom N, O, or S, and wherein the radical may be a carbon radical orheteroatom radical (i.e., the heteroatom may appear in the middle or atthe end of the radical), such as —(CH₂)_(y)O— where y is 1 to 12.

The terms “heterocycloalkyl,” “heterocycle,” “hetercyclyl” and“heterocyclic ring” are used interchangeably herein and refer to asaturated or partially unsaturated carbocyclic radical of 3 to 8 ringatoms, wherein at least one of the carbon atoms in the ring issubstituted with a heteroatom selected from N, O, or S, wherein one ormore ring atoms may be optionally substituted independently with one ormore substituents described below. The radical may be a carbon radicalor heteroatom radical. The terms further include fused ring systems thatinclude a heterocycle fused to a saturated or partially unsaturatedcycloalkyl or heterocycloalkyl ring or an aryl or heteroaryl ring.Examples of heterocycloalkyl rings include, but are not limited to,pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino,morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl,azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl,oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl,2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl,dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl,imidazolidinyl, 3-azabicyco[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,azabicyclo[2.2.2]hexanyl, 3H-indolyl quinolizinyl and N-pyridyl ureas.Spiro moieties are also included within the scope of this definition.The foregoing groups, as derived from the groups listed above, may beC-attached or N-attached where such is possible. For instance, a groupderived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl(C-attached). Further, a group derived from imidazole may beimidazol-1-yl (N-attached) or imidazol-3-yl (C-attached). An example ofa heterocyclic group wherein 2 ring carbon atoms are substituted withoxo (═O) moieties is 1,1-dioxo-thiomorpholinyl. The heterocycle groupsherein are unsubstituted or, as specified, substituted in one or moresubstitutable positions with one or more substituents described herein.For example, such heterocycle groups may be optionally substituted with,for example, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro,amino, mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl,mono(C₁-C₆)alkylamino(C₁-C₆)alkyl or di(C₁-C₆)alkylamino(C₁-C₆)alkyl.

The term “aryl” refers to a monovalent aromatic carbocyclic radicalhaving a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), ormultiple condensed rings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl, etc.), which are optionally mono-,di-, or trisubstituted independently with substituents such as halogen,lower alkyl, lower alkoxy, trifluoromethyl, aryl, heteroaryl, andhydroxy. The term “aryl” includes bicyclic radicals comprising anaromatic ring fused to a saturated, partially unsaturated ring, oraromatic carbocyclic or heterocyclic ring.

The term “heteroaryl” refers to a monovalent 5-, 6-, or 7-memberedmonovalent aromatic carbocyclic radical wherein at least one of thecarbon atoms in the ring is substituted with a heteroatom selected fromN, O, or S, and includes fused ring systems (at least one of which isaromatic) of 5-10 atoms. Examples of heteroaryl groups include, but arenot limited to, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Spiromoieties are also included within the scope of this definition.Heteroaryl groups are optionally substituted with one or moresubstituents described herein.

By way of example and not limitation, carbon bonded heterocycles andheteroaryls are bonded at position 2, 3, 4, 5, or 6 of a pyridine,position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of apyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole ortetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole orthiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole,position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine,position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5,6, 7, or 8 of an isoquinoline. Further examples of carbon bondedheterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl,6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl,3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles andheteroaryls are bonded at position 1 of an aziridine, azetidine,pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline,1H-indazole, position 2 of an isoindole, or isoindoline, position 4 of amorpholine, and position 9 of a carbazole, or β-carboline. Still moretypically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl,1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

The term “halogen” represents fluorine, bromine, chlorine, and iodine.

The term “arylalkyl” means an alkyl moiety (as defined above)substituted with one or more aryl moiety (also as defined above). Morepreferred arylalkyl radicals are aryl-C₁₋₃-alkyls. Examples include, butare not limited to, benzyl, phenylethyl and the like.

The term “heteroarylalkyl” means an alkyl moiety (as defined above)substituted with a heteroaryl moiety (also as defined above). Morepreferred heteroarylalkyl radicals are 5- or 6-memberedheteroaryl-C₁₋₃-alkyls. Examples include, but are not limited to,oxazolylmethyl, pyridylethyl and the like.

The term “heterocyclylalkyl” means an alkyl moiety (as defined above)substituted with a heterocyclyl moiety (also defined above). Morepreferred heterocyclylalkyl radicals are 5- or 6-memberedheterocyclyl-C₁₋₃-alkyls. An example includes, but is not limited to,tetrahydropyranylmethyl.

The term “cycloalkylalkyl” means an alkyl moiety (as defined above)substituted with a cycloalkyl moiety (also defined above). Morepreferred cycloalkylalkyl radicals are 5- or 6-memberedcycloalkyl-C₁₋₃-alkyls. Examples include cyclopropylmethyl.

The term “Me” means methyl, “Et” means ethyl, “Bu” means butyl and “Ac”means acetyl.

In general, the various moieties or functional groups of the compoundsof Formula I may be optionally substituted by one or more substituents.Examples of substituents suitable for purposes of this inventioninclude, but are not limited to, oxo, halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, OR¹⁴,—NR¹⁴SO₂R¹⁵, —SO₂NR¹⁴R¹⁵, —C(O)R¹⁴, —C(O)OR¹⁴, —OC(O)R¹⁴, —NR¹⁴C(O)OR¹⁵,—NR¹⁴C(O)R¹⁵, —C(O)NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —NR¹⁴C(O)NR¹⁴R¹⁵,—NR¹⁴C(NCN)NR¹⁴R¹⁵, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl, where R¹⁴ and R¹⁵ are as definedherein.

It is to be understood that in instances where two or more radicals areused in succession to define a substituent attached to a structure, thefirst named radical is considered to be terminal and the last namedradical is considered to be attached to the structure in question. Thus,for example, an arylalkyl radical is attached to the structure inquestion by the alkyl group.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers,diastereomers mixtures, racemic or otherwise, thereof. Accordingly, thisinvention also includes all such isomers, including diastereomericmixtures and pure enantiomers of the Formula I. Diastereomeric mixturescan be separated into their individual diastereomers on the basis oftheir physical chemical differences by methods known to those skilled inthe art, for example, by chromatography or fractional crystallization.Enantiomers can be separated by converting the enantiomer mixture into adiastereomeric mixture by reaction with an appropriate optically activecompound (e.g., alcohol), separating the diastereomers and converting(e.g., hydrolyzing) the individual diastereomers to the correspondingpure enantiomers. The methods for the determination of stereochemistryand the separation of stereoisomers are well known in the art (seediscussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition, J.March, John Wiley and Sons, New York, 1992).

In addition to compounds of the Formula I, the invention also includessolvates, pharmaceutically acceptable prodrugs, pharmaceutically activemetabolites, solvates, and pharmaceutically acceptable salts of suchcompounds.

A “pharmaceutically acceptable prodrug” is a compound that may beconverted under physiological conditions or by solvolysis to thespecified compound or to a pharmaceutically acceptable salt of suchcompound. Prodrugs include compounds wherein an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues (i.e., peptides) is covalently joined through an amide or esterbond to a free amino, hydroxy or carboxylic acid group of compounds ofthe present invention. Amino acid residues include, but are not limitedto, the 20 naturally occurring amino acids commonly designated by threeletter symbols and also includes 4-hydroxyproline, hydroxylysine,demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine,gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithineand methionine sulfone. One preferred prodrug of this invention is acompound of Formula I covalently joined to a phosphate residue. Anotherpreferred prodrug of this invention is a compound of Formula Icovalently joined to a valine residue or an alanine-alanine dipeptide.

Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. As anotherexample, compounds of this invention comprising free hydroxy groups maybe derivatized as prodrugs by converting the hydroxy group into groupssuch as, but not limited to, phosphate ester, hemisuccinate,dimethylaminoacetate, or phosphoryloxymethyloxycarbonyl groups, asoutlined in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamateprodrugs of hydroxy and amino groups are also included, as are carbonateprodrugs, sulfonate esters and sulfate esters of hydroxy groups.Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethylethers wherein the acyl group may be an alkyl ester, optionallysubstituted with groups including, but not limited to, ether, amine andcarboxylic acid functionalities, or where the acyl group is an aminoacid ester as described above, are also encompassed. Prodrugs of thistype are described in J. Med Chem., 1996, 39, 10. More specific examplesinclude replacement of the hydrogen atom of the alcohol group with agroup such as (C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanoyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate).

Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding, but not limited to, ether, amine and carboxylic acidfunctionalities. For example, a prodrug can be formed by the replacementof a hydrogen atom in the amine group with a group such as R-carbonyl,RO-carbonyl, NRR′-carbonyl where R and R′ are each independently(C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, benzyl, or R-carbonyl is a naturalα-aminoacyl or natural α-aminoacyl-natural α-aminoacyl, —C(OH)C(O)OYwherein Y is H, (C₁-C₆)alkyl or benzyl, —C(OYo)Y₁ wherein Y₀ is(C₁-C₄)alkyl and Y₁ is (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl,amino(C₁-C₄)alkyl or mono-N- or di-N,N— (C₁-C₆)alkylaminoalkyl, —C(Y₂)Y₃wherein Y₂ is H or methyl and Y₃ is mono-N- or di-N,N—(C₁-C₆)alkylamino,morpholino, piperidin-1-yl or pyrrolidin-1-yl.

Prodrugs of a compound may be identified using routine techniques knownin the art. Various forms of prodrugs are known in the art. For examplesof such prodrug derivatives, see, for example, a) Design of Prodrugs,edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol.42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) ATextbook of Drug Design and Development, edited by Krogsgaard-Larsen andH. Bundgaard, Chapter 5 “Design and Application of Prodrugs,” by H.Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug DeliveryReviews, 8, 1-38 (1992); d) H. Bundgaard, et al., Journal ofPharmaceutical Sciences, 77:285 (1988); and e) N. Kakeya, et al., Chem.Pharm. Bull., 32: 692 (1984), each of which is specifically incorporatedherein by reference.

A “metabolite” is a pharmacologically active product produced through invivo metabolism of a specified compound or salt or prodrug thereof. Suchproducts may result for example from the oxidation, reduction,hydrolysis, amidation, deamidation, esterification, deesterification,enzymatic cleavage, and the like, of the administered compound. Theinvention also includes products produced by a process comprisingcontacting a compound of this invention with a mammal for a period oftime sufficient to yield a metabolic product thereof.

Metabolites of a compound may be identified using routine techniquesknown in the art. For example, metabolite products typically areidentified by preparing a radiolabelled (e.g., ¹⁴C or ³H) isotope of acompound of the invention, administering it parenterally in a detectabledose (e.g., greater than about 0.5 mg/kg) to an animal such as rat,mouse, guinea pig, monkey, or to man, allowing sufficient time formetabolism to occur (typically about 30 seconds to 30 hours) andisolating its conversion products from the urine, blood or otherbiological samples. These products are easily isolated since they arelabeled (others are isolated by the use of antibodies capable of bindingepitopes surviving in the metabolite). The metabolite structures aredetermined in conventional fashion, e.g., by MS, LC/MS or NMR analysis.In general, analysis of metabolites is done in the same way asconventional drug metabolism studies well-known to those skilled in theart. The metabolite products, so long as they are not otherwise found invivo, are useful in diagnostic assays for therapeutic dosing of thecompounds of the invention.

The term “solvate” refers to an aggregate of a molecule with one or moresolvent molecules.

A “pharmaceutically acceptable salt,” unless otherwise indicated,includes salts that retain the biological effectiveness of the freeacids and bases of the specified compound and that are not biologicallyor otherwise undesirable. A compound of the invention may possess asufficiently acidic, a sufficiently basic, or both functional groups,and accordingly react with any of a number of inorganic or organicbases, and inorganic and organic acids, to form a pharmaceuticallyacceptable salt. Examples of pharmaceutically acceptable salts includethose salts prepared by reaction of the compounds of the presentinvention with a mineral or organic acid or an inorganic base, suchsalts including sulfates, pyrosulfates, bisulfates, sulfites,bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates,metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyn-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,dinitromenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, xylenesulfonates, pheylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates,tartrates, methanesulfonates, propanesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.Since a single compound of the present invention may include more thanone acidic or basic moiety, the compounds of the present invention mayinclude mono, di or tri-salts in a single compound.

If the inventive compound is a base, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method available in theart, for example, treatment of the free base with an acidic compound,particularly an inorganic acid, such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid and the like, or withan organic acid, such as acetic acid, maleic acid, succinic acid,mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid,glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronicacid or galacturonic acid, an alpha hydroxy acid, such as citric acid ortartaric acid, an amino acid, such as aspartic acid or glutamic acid, anaromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid,such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

If the inventive compound is an acid, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method, for example,treatment of the free acid with an inorganic or organic base. Preferredinorganic salts are those formed with alkali and alkaline earth metalssuch as lithium, sodium, potassium, barium and calcium. Preferredorganic base salts include, for example, ammonium, dibenzylammonium,benzylammonium, 2-hydroxyethylammonium, bis(2-hydroxyethyl)ammonium,phenylethylbenzylamine, dibenzyl-ethylenediamine, and the like salts.Other salts of acidic moieties may include, for example, those saltsformed with procaine, quinine and N-methylglusoamine, plus salts formedwith basic amino acids such as glycine, ornithine, histidine,phenylglycine, lysine and arginine.

The compounds of Formula I also include other salts of such compoundswhich are not necessarily pharmaceutically acceptable salts, and whichmay be useful as intermediates for preparing and/or purifying compoundsof Formula I and/or for separating enantiomers of compounds of FormulaI.

The inventive compounds may be prepared using the reaction routes andsynthetic schemes such as in Schemes I-XIX described below, employingtechniques available in the art using starting materials that arereadily available or can be synthesized using methods known in the art.

Scheme I illustrates one method of preparing thiadiazoline intermediatesof the Formula I-3. Thiocarbazide I-1 (Takasugi, J. J., Buckwalter, B.L., European patent EP 1004241) can be condensed with the desired ketoneor aldehyde I-2 in an appropriate organic solvent such as ethanol,methylene chloride, 1,1-diethoxyethane or the like, optionally in thepresence of a suitable acid such as acetic acid, at room temperature orelevated temperatures to give a thiadiazoline of Formula I-3. In oneembodiment, I-1 is combined with I-2 in ethanol at room temperature toafford thiadiazoline I-3, wherein R¹, Ar¹ and Ar² are as defined herein.

Thiadiazolylthiadiazolines of the Formula II-4 can be prepared fromintermediate I-3 as illustrated in Scheme II. One method for generatingthiourea intermediate II-1 comprises reacting intermediate I-3 with anappropriate thiocarbonylating agent such as thiocarbonyldiimidazole orthiocarbonylditriazole in a suitable solvent such as THF,1,2-dichloroethane, methylene chloride, or acetonitrile at elevatedtemperatures, followed by treatment with ammonia. In one embodiment,intermediate I-3 is reacted with thiocarbonyldiimidazole in THF atelevated temperatures (e.g., from 60° C. to reflux) and then treatedwith concentrated aqueous ammonia to afford II-1. Alternatively, II-1can be synthesized via treatment of I-3 with a suitable acylisothiocyanate or alkoxycarbonyl isothiocyanate such as benzoylisothiocyanate, ethoxycarbonyl isothiocyanate, acetyl isothiocyanate or4-chlorobenzoyl isothiocyanate in an appropriate solvent such as THF,methylene chloride, ethanol, acetone, acetonitrile or DMF at elevatedtemperatures to form II-2, where R is alkyl, aryl or alkoxy.

Intermediate II-2 can then be converted to II-1 by removal of the acylor alkoxycarbonyl group with a suitable base such as, but not limitedto, K₂CO₃, NaOH, NaOMe, ammonia or hydrazine in a suitable solvent suchas methanol, ethanol, acetone, THF, or aqueous mixtures of such solventsat elevated temperatures. In one embodiment, I-3 is treated with benzoylisothiocyanate in THF at reflux to afford II-2, which is then subjectedto aqueous K₂CO₃ in methanol with heating (70° C.) to generate II-1.Intermediate II-1 can be converted to II-4 by heating with anappropriate α-haloketone or α-haloaldehyde II-3 in a suitable solventsuch as ethanol, DMF or acetone at elevated temperatures. Optionally, abase such as diisopropylethylamine or triethylamine can be added to thereaction mixture when either II-1 or II-3 bears acid-sensitivefunctionality. In one embodiment, intermediate II-1 is heated (60-70°C.) with II-3 and diisopropylethylamine in ethanol to provide compoundII-4.

For the purposes of Scheme II, R¹, Ar¹ and Ar² are as defined herein, R⁵includes, but is not limited to, H, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, —C(═O)NR¹⁰R¹¹, —C(═O)R¹⁰, —C(O)OR¹⁰, and substitutedforms thereof, and R^(5a) independently includes, but is not limited to,H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, and substituted formsthereof.

Compounds of Formulas III-5 and III-9 can be synthesized as illustratedin Scheme III. To prepare a compound of Formula III-5, intermediate I-3can be reacted with carbonyldiimidazole in a suitable solvent such asTHF or methylene chloride at elevated temperatures to provide III-1.Intermediate III-1 can then be alkylated with a suitable alkylatingagent such as, but not limited to, iodomethane, methyltrifluoromethanesulfonate, or benzyl bromide, in an appropriate solventsuch as acetonitrile or methylene chloride at room temperature orelevated temperatures to produce imidazolium intermediate III-2, whereR′ is alkyl or arylmethyl. In one embodiment, III-1 is alkylated usingiodomethane in acetonitrile. III-4 can be synthesized by treating III-2with an appropriate amine of the Formula III-3 in the presence of a basesuch as triethylamine, diisopropylethylamine or excess III-3 in asuitable solvent such as THF, DMF or methylene chloride. In anotherembodiment, III-2 is subjected to excess III-3 in methylene chloride toafford urea III-4. Urea III-4 can be converted to3-oxazolylthiadiazoline III-5 by a procedure that includes hydrolysis ofthe dialkyl acetal utilizing an appropriate acid such asp-toluenesulfonic acid, TFA or sulfuric acid in a suitableaqueous-organic solvent mixture such as wet acetone, chloroform-water,or wet methanol, followed by isolation of the deprotected intermediate(which can exist as a mixture of aldehyde and hemiacetal species) andsubjecting this crude material to conditions for oxazole formation.Oxazole formation can be achieved under a variety of reaction conditionssuch as, but not limited to: 1) a two-step, one-pot procedure in whichthe first step comprises treatment with a combination of a phosphinesuch as triphenylphosphine, a halogenating reagent such as iodine,bromine, hexachloroethane or 1,2-dibromo-1,1,2,2-tetrachloroethane, anda suitable base such as triethylamine, pyridine, collidine, or2,6-di-tert-butylpyridine in an appropriate solvent such as methylenechloride or acetonitrile, and the second step comprises treatment with asuitable base such as DBU, triethylamine or diisopropylethylamine atroom temperature or elevated temperatures; or 2) POCl₃, SOCl₂, Burgessreagent or like reagents in a suitable solvent such as toluene,pyridine, acetonitrile or THF at elevated temperatures. In oneembodiment, III-4 is heated at elevated temperature (e.g., 70° C.) withp-toluenesulfonic acid in THF-water solvent. The crude product is thenisolated and immediately treated with triphenylphosphine,1,2-dibromo-1,1,2,2-tetrachloroethane and 2,6-di-tert-butylpyridine indichloromethane followed by DBU in acetonitrile to afford III-5.

To prepare a compound of Formula III-9, as shown in Scheme III,imidazolium intermediate III-2 can be converted to urea intermediateIII-7 by treatment with the appropriate amino alcohol III-6 in thepresence of a base such as triethylamine, diisopropylethylamine orexcess III-6 in a suitable solvent such as THF or methylene chloride.Oxidation of III-7 to provide ketone III-8 can be achieved by treatmentwith a suitable oxidizing agent in an appropriate solvent such asmethylene chloride or chloroform. Suitable oxidizing agents include, butare not limited to, DMSO/oxalyl chloride/NEt₃ and Dess-Martinperiodinane. Intermediate III-8 can be converted to III-9 under suitablereaction conditions such as, but not limited to: 1) a two-step, one-potprocedure in which the first step comprises treatment with a combinationof a phosphine such as triphenylphosphine, a halogenating reagent suchas iodine, bromine, hexachloroethane or1,2-dibromo-1,1,2,2-tetrachloroethane, and a suitable base such astriethylamine, pyridine, collidine, or 2,6-di-tert-butylpyridine in anappropriate solvent such as methylene chloride or acetonitrile, and thesecond step comprises treatment with a suitable base such as DBU,triethylamine or diisopropylethylamine at room temperature or elevatedtemperatures; or 2) POCl₃, SOCl₂, Burgess reagent or like reagents in asuitable solvent such as toluene, pyridine, acetonitrile or THF atelevated temperatures.

For the purposes of Scheme III, R¹, Ar¹ and Ar² are as defined herein,R⁵ includes, but is not limited to, H, alkyl, cycloalkyl, alkenyl,alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, —C(═O)NR¹⁰R¹¹, —C(═O)R¹⁰, —C(O)OR¹⁰, and substitutedforms thereof, and R^(5a) independently includes, but is not limited to,H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, and substituted formsthereof.

Scheme IV illustrates a method for preparing3-dihydropyrrol-one-thiadiazolines. Thiadiazolines of Formula IV-1 canbe prepared by reacting intermediate I-3 with 3,4-dihydropyrrol-2-one(where X is a leaving group) in a suitable organic solvent such as THF,ethanol, methylene chloride, 1,1-diethoxyethane, isopropanol or the likeat elevated temperatures (e.g., 60-80° C.). In one embodiment, I-3 isreacted with 5-ethoxy-3,4-dihydropyrrol-2-one (Chem. Pharm. Bull.,22(12), 2999 (1974)) in THF and isopropanol at 80° C. to afford athiadiazoline of Formula IV-1.

For the purposes of Scheme IV, R¹, Ar¹ and Ar² are as defined herein,and R⁵ and R^(5a) independently include, but are not limited to, H,halogen, cyano, nitro, azido, —NR¹⁰R¹¹, —NR¹⁰SO₂R¹³, —SO₂NROR¹¹,—C(═O)R¹⁰, —C(O)OR¹⁰, —OC(═O)R¹⁰, —NR¹⁰C(═O)OR¹³, —NR¹⁰C(═O)R¹¹,—C(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹³, —SO₂R¹³, SO₂NHC(═O)R¹⁰,—NR¹⁰C(═O)NR¹¹R¹², —NR¹⁰C(NCN)NR¹¹R¹², —OR¹⁰, alkyl, cycloalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, and substituted forms thereof.

Scheme V illustrates a method of preparing3-(4,5-dihydrothiazol-2-yl)-thiadiazolines of Formula V-2. IntermediateV-1 can be prepared from I-3 in a manner similar to the preparation ofII-1 in Scheme II. In one embodiment, I-3 is reacted withthiocarbonyldiimidazole in THF at reflux and then treated with2-bromoethylamine at reflux to afford V-1 where X is bromine.Optionally, a base such as diisopropylethylamine or triethylamine can beadded in the presence of acid-sensitive functionality. Intermediate V-1,where X is a leaving group, can be converted to a thiadiazoline V-2 witha suitable base such as, but not limited to, a tertiary amine, K₂CO₃,NaOMe, or NaOH, or by heating intermediate V-1 at elevated temperaturesin a suitable organic solvent such as THF, ethanol, methylene chloride,1,1-diethoxyethane, isopropanol or the like. In one embodiment, V-1 isheated at elevated temperatures (e.g., 70-90° C.) in THF to afford athiadiazoline of Formula V-2.

For the purposes of Scheme V, R¹, Ar¹ and Ar² are as defined herein R⁵and R^(5a) independently include, but are not limited to, H, alkyl,cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, —C(═O)NR¹⁰R¹¹,—C(═O)R¹⁰, —C(O)OR¹⁰, and substituted forms thereof.

Scheme VI illustrates methods for preparing5-(1,3,4-thiadiazol-3(2H)-yl)-1,3,4-oxadiazoles. According to onemethod, intermediate III-2 is reacted with the appropriate hydrazide,thiohydrazide, semicarbazide or thiosemicarbazide and a suitable basesuch as triethylamine or diisopropylethylamine in an organic solventsuch as DCM, THF, DCE, acetone, DMF or acetonitrile to givethiadiazoline VI-1 where Y is O or S and P is R⁵ or NR¹⁰R¹¹, where R¹⁰and R¹¹ are as defined herein. For the purposes of Scheme VI, R⁵includes, but is not limited to, H, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, and substituted forms thereof. Thiadiazoline VI-2 canthen be prepared by reacting intermediate VI-1 with POCl₃, EDCI, Mel orother activating agent with the optional addition of a suitable basesuch as triethylamine or diisopropylethylamine in a suitable organicsolvent such as DCE, DCM, DMF, THF or acetonitrile. In one embodiment,intermediate III-2 is reacted with acetohydrazide and triethylamine inDCM to give intermediate VI-1, where P is methyl and Y is oxygen.Intermediate VI-1 is then reacted with POCl₃ and diisopropylethylaminein DCE at room temperature to give oxadiazole VI-2.

In another embodiment as shown in Scheme VI, intermediate III-2 can bereacted with a thiosemicarbazide in a suitable organic solvent such asTHF, MeCN, DCM or DCE at room temperature to give intermediate VI-1where Y is sulfur and P is NR¹⁰R¹¹. Intermediate VI-1 is then treatedwith EDCI or other suitable activating agent to give amino oxadiazoleVI-5, wherein R¹, Ar¹, Ar², R¹⁰ and R¹¹ are as defined herein.

Alternatively, as also shown in Scheme VI, intermediate III-2 can betreated with hydrazine and an appropriate base such as triethylamine,diisopropylethylamine or excess hydrazine in a suitable organic solventsuch as DCM, THF, DCE, acetone, DMF or acetonitrile to give intermediateVI-3. Intermediate VI-3 can then be treated with BrCN in the presence ofa suitable base such as triethylamine, diisopropylethylamine, K₂CO₃,NaHCO₃, or NaOAc in an appropriate organic solvent such as DCE, DCM,THF, ether, or acetonitrile at room temperature or elevated temperaturesto give oxadiazole VI-4. Functionalization of the amino group affordsoxadiazoles VI-5 (Arzneimittel-Forschung (2003), 53(5), 301-306;Heterocyclic Communications (2003), 9(2), 199-202;Arzneimittel-Forschung (2003), 53(1), 44-52).

5-(1,3,4-thiadiazol-3(2H)-yl)-1,3,4-thiadiazoles of Formula VII-2 can beprepared from intermediate I-3 as illustrated in Scheme VII. One methodincludes preparing intermediate VII-1 by reacting I-3 with anappropriate thiocarbonylating agent such as thiocarbonyldiimidazole orthiocarbonylditriazole in a suitable solvent such as THF,1,2-dichloroethane, methylene chloride, or acetonitrile at elevatedtemperatures followed by treatment with the appropriate hydrazide orsemicarbazide to provide intermediate VII-1. Thiadiazoline VII-2 can beprepared by reacting intermediate VII-1 with POCl₃, EDCI, Mel or otheractivating agent, optionally in the presence of a suitable base such astriethylamine or diisopropylethylamine, in a suitable organic solventsuch as DCE, DCM, DMF, THF or acetonitrile. Alternatively, VII-1 can besynthesized via VII-3, which can be prepared by reacting I-3 with anappropriate thiocarbonylating agent such as thiocarbonyldiimidazole orthiocarbonylditriazole in a suitable solvent such as THF,1,2-dichloroethane, methylene chloride, or acetonitrile at elevatedtemperatures followed by addition of hydrazine. Treatment of VII-3 witha suitable isocyanate, anhydride or acyl chloride in an appropriatesolvent such as THF, methylene chloride, ethanol, acetone, acetonitrileor DMF provides intermediate VII-1. In one embodiment, intermediate I-3is reacted with thiocarbonyldiimidazole in THF at elevated temperatures(e.g., from 60° C. to reflux) and then treated with hydrazine to affordintermediate VII-3. Intermediate VII-3 is then reacted with an acidanhydride in dichloromethane to give VII-1, which is treated with POCl₃and diisopropylethylamine in DCE at room temperature to give thiadiazoleVII-2.

Alternatively, as shown in Scheme VII,5-(1,3,4-thiadiazol-3(2H)-yl)-1,3,4-thiadiazole VII-2 can be preparedthrough thiadiazoline VII-3 upon treatment with 1,1,1-trialkoxyalkanesand a suitable acid such as p-toluenesulfonic acid, camphorsulfonic acidor TFA in neat 1,1,1-trialkoxyalkane or in a suitable solvent such asDMF, DCM, or alcoholic solvent at elevated temperatures. In anotherembodiment, VII-3 is reacted with trimethyl orthoformate and catalyticamount of p-toluenesulfonic acid at 60° C. to afford VII-2 where R⁵ ishydrogen.

Intermediate VII-3 can also be treated with BrCN in the presence of asuitable base such as triethylamine, diisopropylethylamine, K₂CO₃,NaHCO₃ or NaOAc in an appropriate organic solvent such as DCE, DCM, THF,ether, or acetonitrile at room temperature or elevated temperatures togive thiadiazole VII-4. Functionalization of the amino group affordsthiadiazoles VII-5 (Arzneimittel-Forschung (2003), 53(5), 301-306;Heterocyclic Communications (2003), 9(2), 199-202;Arzneimittel-Forschung (2003), 53(1), 44-52).

For the purposes of Scheme VII, R¹, Ar¹, Ar², R¹⁰ and R¹¹ are as definedherein, and R⁵ includes, but is not limited to, H, —NR¹⁰R¹¹, alkyl,cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, and substituted formsthereof.

Scheme VIII illustrates methods for preparing5-(1,3,4-thiadiazol-3(2H)-yl)-1,2,4-oxadiazoles of Formula VIII-3.Thiadiazoline VIII-1 can be prepared by reacting intermediate III-2 withN-hydroxyamidine or N′-hydroxyguanidine in a suitable organic solventsuch as DCM, THF, DCE, acetone, DMF or acetonitrile. Intermediate VIII-1can be converted to thiadiazoline VIII-3 by treatment with a dehydratingagent or by heating. Alternatively, VIII-1 can be transformed to VIII-2,wherein OR′ is a leaving group, by treatment with acetic anhydride,acetyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride orlike reagents. Intermediate VIII-2 can be cyclized to thiadiazolineVIII-3 by treatment with a dehydrating agent or by heating. In oneembodiment, intermediate III-2 is reacted with N-hydroxyacetamidine inDCM to give intermediate VIII-1 wherein R⁵ is methyl. IntermediateVIII-1 is treated with acetic anhydride in DCM to afford VIII-2, whereR′ is C(O)Me and R⁵ is methyl. Intermediate VIII-2 is then heated inpyridine at 80° C. to give thiadiazoline VIII-3.

For the purposes of Scheme VIII, R¹, Ar¹, and Ar² are as defined herein,and R⁵ includes, but is not limited to, H, —NR¹⁰R¹¹, alkyl, cycloalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, and substituted forms thereof.

Thiadiazolylthiadiazolines of the Formula IX-2 can be prepared fromintermediate II-1 as illustrated in Scheme IX. Intermediate II-1 can beconverted to IX-2 by heating with an appropriate cyclic ketone X-1,wherein X is halogen or other suitable leaving group, Y is oxygen,sulfur, —S(O)—, —S(O)₂—, a substituted nitrogen group or an optionallysubstituted carbon group, n is an integer from 1 to 4 and p is aninteger from 1 to 4, in an appropriate solvent such as ethanol, DMF oracetone at elevated temperatures to provide IX-2. Appropriate cyclicketones IX-1 include, but are not limited to, 2-chlorocyclohexanone,2-chlorocyclopentanone and tert-butyl3-bromo-4-oxopiperidine-1-carboxylate. Optionally, a base such asdiisopropylethylamine or triethylamine can be added to the reactionmixture when II-1 bears acid-sensitive functionality. Alternatively,compounds of the Formula IX-2 may be synthesized by a two-step, one-potprocedure in which an appropriate cyclic ketone of the Formula IX-3 isfirst halogenated by treatment with iodine, bromine or other suitablehalogenating agent in a suitable solvent such as ethanol, acetic acid orcarbon tetrachloride at elevated temperatures and then subjected to II-1at elevated temperatures.

For the purposes of Scheme IX, R¹, Ar¹ and Ar² are as defined herein,and R^(e), R^(f), R^(g), and R^(h) include, but are not limited to, Cl,F, cyano, nitro, azido, —OR¹⁰, —NR¹⁰R¹¹, —NR¹⁰SO₂R¹³, SO₂NR¹⁰R¹¹,—C(═O)R¹⁰, —C(O)OR¹⁰, —OC(═O)R¹⁰, —NR¹⁰C(═O)OR¹³, —NR¹⁰C(═O)R¹¹,—C(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹³, SO₂R¹³, —SO₂NHC(═O)R¹⁰—NR¹⁰C(═O)NR¹¹R¹²,—NR¹⁰C(NCN)NR¹¹R¹², alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,and substituted forms thereof.

Triazolylthiadiazolines of the Formula X-4 can be prepared fromintermediate II-1 as illustrated in Scheme X. Intermediate II-1 may beacylated with the appropriate acyl halide or acid anhydride in asuitable solvent such as THF, methylene chloride, acetone, acetonitrileor DMF to form X-1. Alternatively, X-1 may be synthesized in a mannersimilar to that of intermediate II-2 as shown in Scheme II. IntermediateX-1 can then be alkylated to form X-2, where R′ is an alkyl group, bytreatment with methyl iodide, methyl trifluoromethanesulfonate or othersuitable alkylating agent in the presence of a suitable base such assodium carbonate, potassium carbonate, NaOH, or Ag₂O, in an appropriatesolvent such as acetone, acetonitrile, THF, DMF or methanol. X-2 canthen be treated with a hydrazine of formula X-3 in a suitable solventsuch as ethanol, DMF, THF or acetonitrile at room temperature or atelevated temperatures to afford triazole X-4 as the predominant product.When R⁶ is hydrogen, X-4 or a tautomer of X-4 is obtained. In oneembodiment, I-3 is treated with benzoyl isothiocyanate in THF at refluxas shown in Scheme II to give X-1 wherein R⁵ is phenyl. Alkylation ofX-1 with methyl iodide and sodium carbonate in THF affords X-2 whereinR′ is methyl. Treatment of X-2 with hydrazine in ethanol provides X-4wherein R⁶ is hydrogen.

For the purposes of Scheme X, R¹, Ar¹ and Ar² are as defined herein, R⁵includes, but is not limited to, H, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, and substituted forms thereof; and R⁶ may include,but is not limited to, H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, and substituted forms thereof.

Scheme XI illustrates a method for preparing pyridinyl-thiadiazolinesand pyrimidyl-thiadiazolines, using pyridine based analog XI-1 as shown,or an appropriately substituted pyrimidine. Substituted thiohydrazidesof formula XI-3, can be readily formed by reaction of XI-1 with anappropriate conjugate thioester XI-2, in an appropriate solvent such asethanol, DMF, THF, water or mixtures at room or below (for example, at atemperature ranging from −10° C. to 30° C.) under basic conditions suchas, potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine and similar entities. Thiadiazolines of Formula XI-4 can beprepared by reacting intermediate XI-3 with an appropriately substitutedaldehyde or ketone I-2 in a suitable organic solvent such as THF,ethanol, methylene chloride, 1,1-diethoxyethane, isopropanol or thelike, at a temperature ranging from, for example, 23-80° C. In oneembodiment, XI-3 is reacted with benzaldehyde (Acta Chem. Scand. (14),789, (1960); J. Chem. Soc. Perkin Trans I (2), 360 (1981)) in ethanol,with catalytic hydrochloric acid, at a temperature of, for example, 23°C., to afford a thiadiazoline of Formula XI-4.

For the purposes of Scheme XI, R¹, Ar¹ and Ar² are as defined herein,R_(i), R_(j), R_(k), and R_(l) independently include, but are notlimited to, H, halogen, cyano, nitro, azido, —NR¹⁰R¹¹, —NR¹⁰SO₂R¹³,—SO₂NR¹⁰R¹¹, —C(═O)R¹⁰, —C(O)OR¹⁰, —OC(═O)R¹⁰, —NR¹⁰C(═O)OR¹³,—NR¹⁰C(═O)R¹¹, —C(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹³, —SO₂R¹³, —SO₂NHC(═O)R¹⁰,—NR¹⁰C(═O)NR¹¹R¹², —NR¹⁰C(NCN)NR¹¹R¹², —OR¹⁰, alkyl, cycloalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, and substituted forms thereof.

Scheme XII illustrates a method for preparing bicyclicpyridinyl-thiadiazolines and bicyclic pyrimidinyl-thiadiazolines, usingappropriately substituted pyridinyl hydrazines XII-1 as depicted orsimilarly substituted pyrimidinyl hydrazines. Intermediate XII-1 can beconverted to XII-2 wherein Y is oxygen, sulfur, —S(O)—, —S(O)₂—, asubstituted nitrogen group or an optionally substituted carbon group, nis an integer from 1 to 4 and p is an integer from 1 to 4; X is nitrogenor an optionally substituted carbon group, by reaction with anappropriate thioester XI-2, in an appropriate solvent such as ethanol,DMF, THF, water or mixtures at or below room temperature (for examplebetween −10° C. to 30° C.) utilizing bases such as, potassium carbonate,sodium carbonate, sodium bicarbonate, triethylamine and similarentities. Thiadiazolines of Formula XII-3 can be prepared by reactingintermediate XII-2 with an appropriately substituted aldehyde or ketoneI-2 in a suitable organic solvent such as THF, ethanol, methylenechloride, 1,1-diethoxyethane, isopropanol or the like at a temperatureranging, for example, from 23-80° C. as described in Scheme XI, andexemplified in (Arkiv Kemi. (9), 255, (1956); Acta Chem. Scand. (14),789, (1960); J Chem. Soc. Perkin Trans I (2), 360 (1981).

For the purposes of Scheme XII, R¹, Ar¹ and Ar² are as defined herein,R_(n), R_(o), R_(p), R_(q), R_(r), and R_(s) independently include, butare not limited to, H, halogen, cyano, nitro, azido, —NR¹⁰R¹¹,—NR¹⁰SO₂R¹³, —SO₂NR¹⁰R¹¹, —C(═O)R¹⁰, —C(O)OR¹⁰, —OC(═O)R¹⁰,—NR¹⁰C(═O)OR¹³, —NR¹⁰C(═O)R¹¹, —C(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹³, —SO₂R¹³,—SO₂NHC(═O)R¹⁰, —NR¹⁰C(═O)NR¹¹R¹², —NR¹⁰C(NCN)NR¹¹R¹², —OR¹⁰, alkyl,cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, and substituted formsthereof.

Scheme XIII illustrates a method of preparing compounds of the FormulasXIII-4, XIII-5, XIII-6 and XIII-7. XIII-1 can be synthesized in a mannersimilar to that previously described in the above Schemes. NitrileXIII-1 can be converted to imidate XIII-2 wherein Q is oxygen bytreatment with an anhydrous solution of HCl in methanol, ethanol orother appropriate alcohol at lowered or ambient temperatures. XIII-1 canbe converted to thioimidate XIII-2 wherein Q is sulfur by treatment withHCl and the appropriate thiol in neat thiol or a suitable solvent suchas methanol, ethanol, ether or benzene. In certain embodiments, XIII-1is subjected to anhydrous ethanolic HCl at 0° C. and allowed to warm toroom temperature to afford the hydrochloride salt of XIII-2 wherein Q isoxygen and R^(d) is ethyl. XIII-2 can then be converted to amidineXIII-3 by treatment with ammonia or the appropriate amine in ethanol,methanol or other appropriate solvent. In certain embodiments, XIII-2 istreated with an amine in methanol at room temperature to afford XIII-3or a tautomer thereof. XIII-4 can be obtained by subjecting thehydrochloride salt XIII-2 to cyanamide in alcoholic solvent, followed bytreatment with triethylamine or other suitable base and the appropriateamine. Alternatively, XIII-4 can be generated from XIII-3 by treatmentwith cyanogen bromide or cyanogen chloride and triethylamine or othersuitable base in an appropriate solvent such as ethanol, acetonitrile,chloroform or DMF. XIII-5 is synthesized from XIII-2 by treatment withan alkoxyamine, hydroxylamine, or a salt thereof in the presence oftriethylamine or other suitable base in ethanol, methanol, or othersuitable solvent. In certain embodiments, XIII-2, wherein Q is oxygenand R^(d) is ethyl is treated with the appropriate alkoxyaminehydrochloride in ethanol at room temperature to afford XIII-5 whereinR¹⁸ is alkyl. XIII-6 can be produced from XIII-2 by subjecting XIII-2 tothe appropriate mono-substituted amine at room temperature or elevatedtemperature in ethanol, methanol, or other appropriate solvent.

Scheme XIV illustrates a method of preparing compounds of the FormulasXIV-2, XIV-3 and XIV-4. Amines of the formula XIV-1 are prepared in amanner similar to that described in the above Schemes. Amine XIV-1 canbe converted to XIV-2 by treatment with a guanidinylating reagent suchas, but not limited to, a substituted or unsubstitutedS-methylisothiourea, carbodiimide,3,5-dimethyl-1H-pyrazole-1-carboxamidine or aminoiminomethanesulfonicacid reagent in an appropriate solvent and at elevated temperature ifnecessary. Alternatively, XIV-2 can be prepared by subjecting XIV-1 to aN-protected guanidinylating reagent such as, but not limited to,di-Boc-S-methylisothiourea, di-CBz-triflylguanidine, orN,N-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine in a suitablesolvent followed by subsequent removal of the protecting groups underthe appropriate conditions to provide XIV-2 or a tautomer thereof. Incertain embodiments, amine XIV-1 is treated withN,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine intetrahydrofuran, followed by treatment with hydrochloric acid in dioxaneto remove the tert-butoxycarbonyl protecting groups to afford XIV-2 or atautomer thereof wherein R¹⁸, R²⁰ and R²¹ are hydrogen. Compound XIV-3can be obtained from amine XIV-1 by treatment with the appropriateimidate or imidate salt in combination with a suitable base, in analcoholic solvent at elevated temperature. In certain embodiments, amineXIV-1 is treated with the hydrochloride salt of an ethyl imidate andtriethylamine in refluxing anhydrous ethanol to afford XIV-3 or atautomer thereof. Compound XIV-4 is prepared by treatment of amine XIV-1with the appropriate cyanoimidate or cyanoimidate salt in combinationwith a suitable base, in an alcoholic solvent. In certain embodiments,amine XIV-1 is treated with an N-cyano ethyl imidate hydrochloride andtriethylamine in anhydrous ethanol to afford XIV-4 or a tautomerthereof.

Scheme XV illustrates a method of preparing compounds of the FormulaXV-2. Amine XIV-I can be converted to compound XV-1 by treatment withcyanogen bromide or cyanogen chloride in the presence of a suitable baseand appropriate solvent. In certain embodiments, amine XIV-1 is treatedwith cyanogen bromide and triethylamine in methylene chloride. CompoundXV-2 can be prepared by treatment of compound XV-1 with excess of analkoxyamine or alkoxyamine salt in the presence of an appropriate basein a suitable solvent optionally at elevated temperatures. In certainembodiments, XV-1 is treated with excess alkoxyamine hydrochloride saltand triethylamine in ethanol at reflux temperature to provide XV-2 or atautomer thereof.

Scheme XVI illustrates a method of preparing compounds of the FormulasXVI-1 and XVI-2. Compound XVI-1 can be prepared in one step from amineXIV-1 by treatment with a cyano-guanidinylating reagent such as, but notlimited to, an N-cyanocarbamimidate, anS-alkyl-N-cyanocarbamimidothioate, or dicyanamide salt. Alternatively,compound XVI-1 can be synthesized in a two-step procedure from XIV-1 byinitial treatment with a reagent including, but not limited to, anN-cyanocarbonimidate or an N-cyanocarbonimidodithioate, optionally inthe presence of a suitable base, followed by subsequent treatment withammonia or the appropriate amine. In certain embodiments, thehydrochloride salt of amine XIV-1 is subjected todiphenylcyanocarbonimidate and triethylamine in isopropanol at roomtemperature, followed by treatment with ammonia or the appropriate aminein methanol at reflux temperature. Compound XVI-2 can be prepared bytreatment of compound XVI-1 with acid and water in a suitable solvent.In certain embodiments, compound XVI-1 is treated with hydrochloric acidin methanol and water to provide compound XVI-2 or a tautomer thereof.

Scheme XVII illustrates a method of preparing compounds of the FormulasXVII-2 and XVII-3. Alkoxyamines of the formula XVII-I can be prepared bya similar route to the preparation of amines of the formula XIV-1 usingthe appropriate N-protected ketone precursor. Compound XVII-2 can beprepared by treatment of alkoxyamine XVII-1 with the appropriate imidateor imidate salt in combination with a suitable base, in an alcoholicsolvent at elevated temperature. In certain embodiments, alkoxyamineXVII-1 is treated with the hydrochloride salt of an ethyl imidate andtriethylamine in refluxing absolute ethanol to afford XVII-2 or atautomer thereof. Compound XVII-3 can be prepared by treatment ofalkoxyamine XVII-1 with a guanidinylating reagent such as, but notlimited to, a substituted or unsubstituted S-methylisothiourea,carbodiimide, 3,5-dimethyl-1H-pyrazole-1-carboxamidine oraminoiminomethanesulfonic acid reagent in the appropriate solvent and atelevated temperature if necessary. Alternatively, XVII-3 can be preparedby subjecting XVII-1 to a N-protected guanidinylating reagent such as,but not limited to, di-Boc-S-methylisothiourea, di-CBz-trifylguanidine,or N,N-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine in asuitable solvent followed by removal of the protecting groups under theappropriate conditions to provide XVII-3 or a tautomer thereof. Incertain embodiments, alkoxyamine XVII-1 is treated withN,N-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine intetrahydrofuran, followed by treatment with hydrochloric acid in dioxaneto remove the tert-butoxycarbonyl protecting groups to afford XVII-3 ora tautomer thereof wherein R¹⁸, R²⁰ and R²¹ are hydrogen.

Scheme XVIII illustrates a method of preparing compounds of the FormulasXVIII-2 and XVIII-3. Alkoxyamines of the formula XVIII-I can be preparedby a similar route to the preparation of amines of the formula XIV-1using the appropriate N-protected ketone precursor. Compound XVIII-2 canbe prepared by treatment of alkoxyamine XVIII-1 with the appropriateimidate or imidate salt in combination with a suitable base, in analcoholic solvent at elevated temperature. In certain embodiments,alkoxyamine XVIII-1 is treated with the hydrochloride salt of an ethylimidate and triethylamine in refluxing absolute ethanol to affordXVIII-2 or a tautomer thereof. Compound XVIII-3 can be prepared bytreatment of alkoxyamine XVIII-1 with a guanidinylating reagent such as,but not limited to, a substituted or unsubstituted S-methylisothiourea,carbodiimide, 3,5-dimethyl-1H-pyrazole-1-carboxamidine oraminoiminomethanesulfonic acid reagent in the appropriate solvent and atelevated temperature if necessary. Alternatively, XVIII-3 can beprepared by subjecting XVIII-1 to a N-protected guanidinylating reagentsuch as, but not limited to, di-Boc-S-methylisothiourea,di-CBz-trifylguanidine, orN,N-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine in a suitablesolvent followed by removal of the protecting groups under theappropriate conditions to provide XVIII-3 or a tautomer thereof. Incertain embodiments, alkoxyamine XVIII-1 is treated withN,N-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine intetrahydrofuran, followed by treatment with hydrochloric acid in dioxaneto remove the tert-butoxycarbonyl protecting groups to afford XVIII-3wherein R¹⁸, R²⁰ and R²¹ are hydrogen.

Scheme XIX illustrates a method of preparing compounds of the FormulasXIX-2 and XIX-3. Hydrazines of the formula XIX-1 can be prepared by asimilar route to the preparation of amines of the formula XIV-1 usingthe appropriate N-protected ketone precursor. Compound XIX-2 can beprepared by treatment of hydrazine XIX-1 with the appropriate imidate orimidate salt in combination with a suitable base, in an alcoholicsolvent at elevated temperature. In certain embodiments, hydrazine XIX-1is treated with the hydrochloride salt of an ethyl imidate andtriethylamine in refluxing absolute ethanol to afford XIX-2 or atautomer thereof. Compound XIX-3 can be prepared by treatment ofhydrazine XIX-1 with a guanidinylating reagent such as, but not limitedto, a substituted or unsubstituted S-methylisothiourea, carbodiimide,3,5-dimethyl-1H-pyrazole-1-carboxamidine or aminoiminomethanesulfonicacid reagent in the appropriate solvent and at elevated temperature ifnecessary. Alternatively, XIX-3 can be prepared by subjecting XIX-1 to aN-protected guanidinylating reagent such as, but not limited to,di-Boc-S-methylisothiourea, di-CBz-trifylguanidine, orN,N-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine in a suitablesolvent followed by removal of the protecting groups under theappropriate conditions to provide XIX-3 or a tautomer thereof. Incertain embodiments, hydrazine XIX-1 is treated withN,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine intetrahydrofuran, followed by treatment with hydrochloric acid in dioxaneto remove the tert-butoxycarbonyl protecting groups to afford XIX-3wherein R¹⁸, R²⁰ and R²¹ are hydrogen.

In the preparation of some analogues such as described in Schemes I-XIX,the use of appropriate protecting groups for functionality containedwithin the various substituents may be necessary. In these cases,deprotection of said functionality can be accomplished using standardmethods known by and available to those skilled in the art.

The compounds of the invention find use in a variety of applications. Aswill be appreciated by those skilled in the art, mitosis may be alteredin a variety of ways. That is, one can affect mitosis either byincreasing or decreasing the activity of a component in the mitoticpathway. Stated differently, mitosis may be affected (e.g., disrupted)by disturbing equilibrium, either by inhibiting or activating certaincomponents. Similar approaches may be used to alter meiosis.

In one embodiment, the compounds of the invention are used to modulatemitotic spindle formation, thus causing prolonged cell cycle arrest inmitosis. The term “modulate” as used herein means altering mitoticspindle formation, including increasing and decreasing spindleformation. The term “mitotic spindle formation” as used herein refers toorganization of microtubules into bipolar structures by mitotickinesins. “Mitotic spindle dysfunction” refers to mitotic arrest andmonopolar spindle formation.

The compounds of the invention are useful to bind to and/or modulate theactivity of a mitotic kinesin. In an embodiment, the mitotic kinesin isa member of the bimC subfamily of mitotic kinesins as described in U.S.Pat. No. 6,284,480, which is incorporated herein by reference. In afurther embodiment, the mitotic kinesin is human KSP, although theactivity of mitotic kinesins from other organisms may also be modulatedby the compounds of the present invention. In this context, modulatemeans either increasing or decreasing spindle pole separation, causingmalformation, i.e., splaying, of mitotic spindle poles, or otherwisecausing morphological perturbation of the mitotic spindle. Also includedwithin the definition of KSP for these purposes are variants and/orfragments of KSP. In addition, other mitotic kinesins may be inhibitedby the compounds of the present invention.

The compounds of the invention are useful for treating diseases andconditions caused by abnormal cell growth or cellular proliferation.Disease states which can be treated by the methods and compositionsprovided herein include, but are not limited to, cancer, autoimmunedisease, arthritis, graft rejection, inflammatory bowel disease, andproliferation induced after medical procedures, including, but notlimited to, surgery, angioplasty, and the like. It is appreciated thatin some cases the cells may not be in a hyperproliferative orhypoproliferative state (abnormal state), but still require treatment.For example, during wound healing, cells may be proliferating“normally”, but proliferation enhancement may be desired. Similarly, inthe agriculture arena, cells may be in a “normal” state, butproliferation modulation may be desired to enhance a crop by directlyenhancing growth of a crop, or by inhibiting the growth of a plant ororganism which adversely affects the crop. Thus, in one embodiment, theinvention herein includes application to cells or individuals that areafflicted or may eventually become afflicted with any one of thesedisorders or states.

The invention also provides pharmaceutical compositions for treating ahyperproliferative disorder in a mammal, which comprise atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug, metabolite or solvatethereof, and a pharmaceutically acceptable carrier. In one embodiment,said pharmaceutical composition is for the treatment of ahyperproliferative disorder such as cancer, including, but not limitedto, skin, brain, lung, squamous cell, bladder, gastric, pancreatic,breast, head, neck, renal, kidney, ovarian, prostate, colorectal,esophageal, testicular, gynecological, cardiac, liver, bone, meninges,spinal cord, blood, skin, adrenal and thyroid cancer.

The compounds of the present invention may also be useful as antifungalagents, by modulating the activity of the fungal members of the bimCkinesin subgroup, as described in U.S. Pat. No. 6,284,480.

The invention also relates to a method of treating a hyperproliferativedisorder in a mammal, comprising administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug, metabolite or solvatethereof. In one embodiment, said method relates to the treatment ofcancer such as brain, lung, squamous cell, bladder, gastric, pancreatic,breast, head, neck, renal, kidney, ovarian, prostate, colorectal,esophageal, testicular, gynecological, cardiac, liver, bone, meninges,spinal cord, blood, skin, adrenal or thyroid cancer.

Patients that can be treated with compounds of the present invention, orpharmaceutically acceptable salts, prodrugs, metabolites or solvates ofsaid compounds, according to the methods of this invention include, forexample, patients that have been diagnosed as having lung cancer, bonecancer, CMML, pancreatic cancer, skin cancer, cancer of the head andneck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer,rectal cancer, cancer of the anal region, stomach cancer, colon cancer,breast cancer, testicular, gynecologic tumors (e.g., uterine sarcomas,carcinoma of the fallopian tubes, carcinoma of the endometrium,carcinoma of the cervix, carcinoma of the vagina or carcinoma of thevulva), Hodgkin's disease, cancer of the esophagus, cancer of the smallintestine, cancer of the endocrine system (e.g., cancer of the thyroid,parathyroid or adrenal glands), sarcomas of soft tissues, cancer of theurethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, solid tumors of childhood, lymphocytic lymphomas, cancer ofthe bladder, cancer of the kidney or ureter (e.g., renal cell carcinoma,carcinoma of the renal pelvis), or neoplasms of the central nervoussystem (e.g., primary CNS lymphoma, spinal axis tumors, brain stemgliomas or pituitary adenomas).

The terms “abnormal cell growth” and “hyperproliferative disorder” areused interchangeably in this application and, unless otherwiseindicated, refer to cell growth that is independent of normal regulatorymechanisms (e.g., loss of contact inhibition). This includes, but is notlimited to, the abnormal growth of: (1) tumor cells (tumors) thatproliferate by expressing a mutated tyrosine kinase or overexpression ofa receptor tyrosine kinase; (2) benign and malignant cells of otherproliferative diseases in which aberrant tyrosine kinase activationoccurs; (3) any tumors that proliferate by receptor tyrosine kinases;(4) any tumors that proliferate by aberrant serine/threonine kinaseactivation; and (5) benign and malignant cells of other proliferativediseases in which aberrant serine/threonine kinase activation occurs.

The term “treating,” as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment,” as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above. “Treating” is intended to meanat least the mitigation of a disease condition in a mammal, such as ahuman, and includes, but is not limited to, modulating and/or inhibitingthe disease condition; and/or alleviating the disease condition.

The compounds of this invention may be used alone or in combination withother drugs and therapies used in the treatment of disease states whichwould benefit from the inhibition of mitotic kinesins. Accordingly,another aspect of this invention provides a method for treating ahyperproliferative disorder in a mammal that comprises administering tosaid mammal a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutically acceptable salt, prodrug,metabolite or solvate thereof, in combination with an anti-tumor agentsuch as, but not limited to:

(i) antiproliferative/anti-neoplastic drugs and combinations thereof, asused in medical oncology, such as alkylating agents (for example,cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan,chlorambucil, busulphan and nitrosoureas); anti-metabolites (forexample, antifolates such as such as fluoropyrimidines like5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosinearabinside, hydroxyurea, or, one of the preferred anti-metabolitesdisclosed in European Patent Application No. 239362 such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid); antitumor antibiotics (for example, anthracyclines likeadriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin,mitomycin-C, dactinomycin and mithramycin); antimitotic agents (forexample, vinca alkaloids like vincristine, vinblastine, vindesine andvinorelbine and taxoids like taxol and taxotere); and topoisomeraseinhibitors (for example epipodophyllotoxins like eptoposide andteniposide, amsacrine, topotecan and campothecin);

(ii) cytostatic agents such as anti-estrogens (for example, tamoxifen,toremifene, raloxifene, droloxifene and iodoxyfene), estrogen receptordown regulators (for example, fulvestratrant), anti-androgens (forexample, bicalutamide, flutamide, nilutamide, cyproxerone acetate andCasodex™(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide)),LHRH antagonists or LHRH agonists (for example, goserelin, leuporelinand buserelin), progestogens (for example, megestrol acetate), aromataseinhibitors (for example, asanastrozole, letrozole, vorazole andexemestane) and inhibitors of 5α-reductase such as finasteride;

(iii) agents which inhibit cancer cell invasion (for example,metalloproteinase inhibitors like marimastat and inhibitors of urokinaseplasminogen activator receptor function);

(iv) inhibitors of growth factor function like growth factor antibodies,growth factor receptor antibodies (for example, the anti-erbB2 antibodytrastumuzab [Herceptin™] and the anti-erbB1 antibody cetuximab [C225]),farnesyl transferase inhibitors, tyrosine kinase inhibitors andserine-threonine kinase inhibitors (for example, inhibitors of theepidermal growth factor family tyrosine kinases such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, AZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine(CI 1033)), inhibitors of the platelet-derived growth factor family andinhibitors of the hepatocyte growth factor family;

(v) anti-angiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor (for example, the anti-vascularendothelial cell growth factor antibody bevacizumab [Avastin™],compounds such as those disclosed in PCT Publication Nos. WO 97/22596,WO 97/30035, WO 97/32856, and WO 98/13354) and compounds that work byother mechanisms (for example, linomide, inhibitors of integrin αvβ3function, MMP inhibitors, COX-2 inhibitors and angiostatin);

(vi) vascular damaging agents such as Combretastatin A4 and compoundsdisclosed in PCT Publication Nos. WO 99/02166, WO 0/40529, WO 00/41669,WO 01/92224, WO 02/04434, and WO 02/08213;

(vii) antisense DNA or RNA therapies (for example, those which aredirected to the targets listed above such as ISIS 2503, and anti-rasantisense);

(viii) gene therapy approaches, including for example GVAX™, approachesto replace aberrant genes such as aberrant p53 or aberrant BRCA1 orBRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such asthose using cytosine deaminase, thymidine kinase or a bacterialnitroreductase enzyme and approaches to increase patient tolerance tochemotherapy or radiotherapy such as multi-drug resistance gene therapy;

(ix) interferon;

(x) immunotherapy approaches, including for example ex-vivo and in-vivoapproaches to increase the immunogenicity of patient tumor cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte-macrophage colony stimulating factor, approaches to decreaseT-cell anergy, approaches to using transfected immune cells such ascytokine-transfected dendritic cells, approaches usingcytokine-transfected tumor cell lines and approaches usinganti-idiotypic antibodies; and

(xi) miscellaneous agents such as intercalating antibiotics, signaltransduction inhibitors, cell cycle inhibitors, enzyme inhibitors,retinoid receptor modulators, proteasome inhibitors, biological responsemodifiers, anti-hormones, targeted antibodies, HMG-CoA reductaseinhibitors, and prenyl-protein transferase inhibitors.

According to this aspect of the invention there is also provided apharmaceutical composition comprising a compound of Formula I as definedherein and an additional anti-tumor agent as defined herein for theconjoint treatment of abnormal cell growth. Such conjoint treatment maybe achieved by way of the simultaneous, sequential or separate dosing ofthe individual components of treatment. Such compositions employ thecompounds of this invention within the dose ranges described herein andthe additional anti-tumor agent within its approved dose range

This invention also relates to a pharmaceutical composition forinhibiting abnormal cell growth in a mammal which comprises an amount ofa compound of Formula I or a pharmaceutically acceptable salt, solvate,metabolite or prodrug thereof, in combination with an amount of achemotherapeutic, wherein the amounts of the compound of Formula I orpharmaceutically acceptable salt, solvate, metabolite or prodrugthereof, and of the chemotherapeutic are together effective ininhibiting abnormal cell growth. Many chemotherapeutics are presentlyknown in the art. In one embodiment, the chemotherapeutic is selectedfrom the group consisting of mitotic inhibitors, alkylating agents,anti-metabolites, antisense DNA or RNA, intercalating antibiotics,growth factor inhibitors, signal transduction inhibitors, cell cycleinhibitors, enzyme inhibitors, retinoid receptor modulators, proteasomeinhibitors, topoisomerase inhibitors, biological response modifiers,anti-hormones, angiogenesis inhibitors, anti-androgens, targetedantibodies, HMG-CoA reductase inhibitors, and prenyl-protein transferaseinhibitors.

This invention further relates to a method for inhibiting abnormal cellgrowth in a mammal or treating a hyperproliferative disorder whichcomprises administering to the mammal an amount of a compound of FormulaI or a pharmaceutically acceptable salt, metabolite, solvate or prodrugthereof, in combination with radiation therapy, wherein the amounts ofthe compound of Formula I or pharmaceutically acceptable salt,metabolite, solvate or prodrug thereof, is in combination with theradiation therapy effective in inhibiting abnormal cell growth ortreating the hyperproliferative disorder in the mammal. Techniques foradministering radiation therapy are known in the art, and thesetechniques can be used in the combination therapy described herein. Theadministration of the compound of the invention in this combinationtherapy can be determined as described herein.

This invention further provides a method for inhibiting proliferation ofcells, comprising contacting said cells with an effective amount of acompound of Formula I or a solvate or pharmaceutically acceptable saltthereof, or a pharmaceutical composition comprising a compound ofFormula I.

It is believed that the compounds of the present invention can renderabnormal cells more sensitive to treatment with radiation for purposesof killing and/or inhibiting the growth of such cells. Accordingly, thisinvention further relates to a method for sensitizing abnormal cells ina mammal to treatment with radiation, which comprises administering tothe mammal an amount of a compound of Formula I or a pharmaceuticallyacceptable salt, solvate, metabolite or prodrug thereof, which amount iseffective in sensitizing abnormal cells to radiation treatment. Theamount of the compound of Formula I or pharmaceutically acceptable salt,solvate, metabolite or prodrug thereof, to be used in this method can bedetermined according to means for ascertaining effective amounts of suchcompounds as described herein or by methods know to those skilled in theart.

The compounds of this invention may be used alone or in combination withother drugs and therapies used in the treatment of disease states whichwould benefit from the inhibition of KSP kinesin. For example, acompound of Formula I or a pharmaceutically acceptable salt, solvate,metabolite or prodrug thereof may be administered to a mammal in needthereof in combination with one or more other anti-tumor substances,including, but not limited to, mitotic inhibitors such as vinblastine;alkylating agents such as cis-platin, carboplatin and cyclophosphamide;anti-metabolites such as 5-fluorouracil, cytosine arabinside andhydroxyurea; one of the preferred anti-metabolites disclosed in EuropeanPatent Application No. 239362 such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid (also known as ZD 1694 and ICI 1694); antisense RNA and DNAoligonucleotides such as G3139, ODN698, and GEM231; growth factorinhibitors; signal transduction inhibitors, such as agents that caninhibit EGFR (epidermal growth factor receptor) responses, such as EGRFantibodies, EGF anitbodies and molecules that are EGFR inhibitors suchas the compounds ZD-1839 (AstraZeneca) and BIBX-1382 (BoehringerIngelheim); VEGF inhibitors such as SU-6668 (Sugen, Inc. of South SanFrancisco, Calif.) or the anti-VEGF monoclonal antibody of Genentech,Inc. of South San Francisco, Calif.; cell cycle inhibitors;intercalating antibiotics such as adriamycin and bleomycin; enzymes, forexample, interferon; retinoid receptor modulators such as bexarotene,ILX23-7553, and N-4-carboxyphenyl retinamide; proteasome inhibitors suchas lactacystin and bortezomib; topoisomerase inhibitors such astopotecan, rebutecan and teniposide; anti-hormone such as anti-estrogenssuch as Nolvadex™ (tamoxifen); anti-androgens such as Casodex™(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide);monoclonal antibody targeted therapeutic agents which have cytotoxicagents or radioisotopes attached to a cancer cell specific or targetcell specific monoclonal antibody; inhibitors of HMG-CoA reductase(3-hydroxy-3-methylglutrayl-CoA reductase) such as simvastatin (ZOCOR®)and atorvastatin (LIPITOR®); prenyl-protein transferase inhibitors;inhibitors of protein kinases that transduce cell cycle checkpointsignals (e.g., ART, ARM, the Chk1 and Chk2 kinases, cdk and cdc kinase)such as 7-hydroxystaurosporin, flavopiridol and CYC202 (Cyclacel); andinhibitors of kinases involved in mitotic progression where such kinasesinclude, but are not limited to, Polo-like kinases and aurora kinase.Such conjoint treatment may be achieved by way of simultaneous,sequential or separate dosing of the individual components of treatment.

The compounds of the present invention may also be used in combinationwith inhibitors of mitotic kinesins. Examples of inhibitors of mitotickinesins, and in particular the human mitotic kinesin KSP, are describedin PCT Publication Nos. WO 00/130,768, WO 01/30768, WO 01/98278, WO03/050,064, WO 03/050,122, WO 03/049,527, WO 03/049,679, WO 03/049,678,WO 03/39460 WO 03/079,973, WO 03/088,903, WO 03/094,839, WO 03/097,053,WO 03/099,211, WO 03/099,286, WO 03/103,575, WO 03/105,855, WO03/106,426, WO 04/032,840, WO 04/034,879, WO 04/037,171, WO 04/039,774,WO 04/055,008, WO 04/058,148, WO 04/058,700 and WO 04/064,741.

The compounds of the present invention may also be used in the treatmentof cancer in combination with compounds that are not anti-tumorcompounds. For example, a compound of this invention may be applied incombination with one or more substances, including, but not limited to,PPAR-γ and PPAR-δ agonists such as proglitazone, rosiglatazone, genetherapy agents, and inhibitors of inherent multi-drug resistance (e.g.p-glycoprotein inhibitors).

A compound of the present invention may also be employed in conjunctionwith anti-emetic agents to treat nausea or emesis, by way ofsimultaneous, sequential or separate dosing of the individual componentsof treatment.

A compound of the present invention may also be administered incombination with an agent useful in the treatment of anemia, such asepoetin, by way of simultaneous, sequential or separate dosing of theindividual components of treatment.

A compound of the present invention may also be administered incombination with an agent useful in the treatment of neutropenia, by wayof simultaneous, sequential or separate dosing of the individualcomponents of treatment. Such a neutropenia treatment agent is, forexample, a hematopoietic growth factor, which regulates the productionand function of neutrophils such as a human granulocyte colonystimulating factor, (G-CSF). An example of a G-CSF is filgrastim.

A compound of the present invention may also be administered incombination with an immunologic-enhancing drug, such as levamisole,isoprinosine and Zadaxin, by way of simultaneous, sequential or separatedosing of the individual components of treatment.

Although the compounds of Formula I are primarily of value astherapeutic agents for use in warm-blooded animals (including humans),they are also useful whenever it is required to inhibit the effects ofKSP kinesin. Thus, they are also useful as pharmacological standards inthe development of new biological tests and in the search for newpharmacological agents.

The invention also provides pharmaceutical compositions comprising acompound of Formula I, or a pharmaceutically acceptable salt,metabolite, solvate or prodrug thereof, and methods of use thereof forinhibiting abnormal cell growth in a mammal, comprising administering toa mammal in need thereof an amount of a compound of Formula I or apharmaceutically acceptable salt, solvate, metabolite, or prodrug,thereof, alone or in combination with an amount of one or moresubstances selected from anti-angiogenesis agents, signal transductioninhibitors, and antiproliferative agents, in amounts effective toinhibit abnormal cell growth.

For example, anti-angiogenesis agents, such as MMP-2(matrix-metalloprotienase 2) inhibitors, MMP-9 (matrix-metalloprotienase9) inhibitors, and COX-II (cyclooxygenase II) inhibitors, can be used inconjunction with a compound or pharmaceutical compositions of thepresent invention. Examples of useful COX-II inhibitors includeCELEBREX™ (alecoxib), valdecoxib, etoricoxib, lumiracoxib androfecoxib). Examples of useful matrix metalloprotienase inhibitors aredescribed in PCT Publication Nos. WO 96/33172, WO 96/27583, WO 98/07697,WO 98/03516, WO 98/34918, WO 98/34915, WO 98/33768, WO 98/30566, WO90/05719, WO 99/52910, WO 99/52889, WO 99/29667, U.S. Pat. No.5,863,949, and U.S. Pat. No. 5,861,510. Preferred MMP-2 and MMP-9inhibitors are those that have little or no activity inhibiting MMP-1.More preferred, are those that selectively inhibit MMP-2 and/or MMP-9relative to the other matrix-metalloproteinases (i.e., MMP-1, MMP-3,MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of treatment.Such combination products employ the compounds of this invention withinthe dose range described herein and the other pharmaceutically activeagent within its approved dose range.

It will be understood that the specific dosage level and frequency ofdosage for any particular subject may be varied and will depend upon avariety of factors including the activity of the specific compound ofFormula I, the species, age, body weight, general health, sex and dietof the subject, the mode and time of administration, rate of excretion,drug combination, and severity of the particular condition, but cannevertheless be routinely determined by one skilled in the art.

This invention also provides compounds of Formula I for use in therapy.An additional aspect of the invention is the use of a compound ofFormula I for the preparation of a medicament for use as a kinesininhibitor.

In order to use a compound of the Formula I, or a pharmaceuticallyacceptable salt, solvate, metabolite or prodrug thereof, for thetherapeutic treatment (including prophylactic treatment) of mammalsincluding humans, it is normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition. According tothis aspect of the invention there is provided a pharmaceuticalcomposition that comprises a compound of the Formula I, or apharmaceutically acceptable salt, solvate, metabolite or prodrug thereofas defined herein, in association with a pharmaceutically acceptablediluent or carrier.

To prepare the pharmaceutical compositions according to this invention,a therapeutically or prophylactically effective amount of a compound ofFormula I or pharmaceutically acceptable salt, solvate, metabolite orprodrug thereof (alone or together with an additional therapeutic agentas disclosed herein) is preferably intimately admixed with apharmaceutically acceptable carrier according to conventionalpharmaceutical compounding techniques to produce a dose. A carrier maytake a wide variety of forms depending on the form of preparationdesired for administration, e.g., oral or parenteral. Examples ofsuitable carriers include any and all solvents, dispersion media,adjuvants, coatings, antibacterial and antifungal agents, isotonic andabsorption delaying agents, sweeteners, stabilizers (to promote longterm storage), emulsifiers, binding agents, thickening agents, salts,preservatives, solvents, dispersion media, coatings, flavoring agents,and miscellaneous materials such as buffers and absorbents that may beneeded in order to prepare a particular therapeutic composition. The useof such media and agents with pharmaceutically active substances is wellknown in the art. Except insofar as any conventional media or agent isincompatible with a compound of Formula I, its use in the therapeuticcompositions and preparations is contemplated. Supplementary activeingredients can also be incorporated into the compositions andpreparations as described herein.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, or intramusculardosing or as a suppository for rectal dosing).

Suitable pharmaceutically-acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil. For example,compositions intended for oral use may also contain, for example, one ormore coloring, sweetening, flavoring and/or preservative agents.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate), anti-oxidants (such as ascorbic acid),coloring agents, flavoring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavoring and coloring agentsmay also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, esters or partial esters derived from fatty acids and hexitolanhydrides (for example sorbitan monooleate) and condensation productsof the said partial esters with ethylene oxide such as polyoxyethylenesorbitan monooleate. The emulsions may also contain sweetening,flavoring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavoring and/or coloring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above.For parenteral formulations, the carrier will usually comprise sterilewater, aqueous sodium chloride solution, 1,3-butanediol, or any othersuitable non-toxic parenterally-acceptable diluent or solvent. Otheringredients including those that aid dispersion may be included. Ofcourse, where sterile water is to be used and maintained as sterile, thecompositions and carriers must also be sterilized. Injectablesuspensions may also be prepared, in which case appropriate liquidcarriers, suspending agents and the like may be employed.

Suppository formulations may be prepared by mixing the active ingredientwith a suitable non-irritating excipient which is solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum to release the drug. Suitable excipients include, forexample, cocoa butter and polyethylene glycols.

Topical formulations, such as creams, ointments, gels and aqueous oroily solutions or suspensions, may generally be obtained by formulatingan active ingredient with a conventional, topically acceptable, vehicleor diluent using conventional procedures well known in the art.

Compositions for administration by insufflation may be in the form of afinely divided powder containing particles of average diameter of, forexample, 30 μm or much less, the powder itself comprising either activeingredient alone or diluted with one or more physiologically acceptablecarriers such as lactose. The powder for insufflation is thenconveniently retained in a capsule containing, for example, 1 to 50 mgof active ingredient for use with a turbo-inhaler device, such as isused for insufflation of the known agent sodium cromoglycate.

Compositions for administration by inhalation may be in the form of aconventional pressurized aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

Compositions for transdermal administration may be in the form of thosetransdermal skin patches that are well known to those of ordinary skillin the art.

For further information on formulations, see Chapter 25.2 in Volume 5 ofComprehensive Medicinal Chemistry (Corwin Hansch; Chairman of EditorialBoard), Pergamon Press 1990.

The amount of a compound of this invention that is combined with one ormore excipients to produce a single dosage form will necessarily varydepending upon the subject treated, the severity of the disorder orcondition, the rate of administration, the disposition of the compoundand the discretion of the prescribing physician. However, an effectivedosage is in the range of about 0.001 to about 100 mg per kg body weightper day, preferably about 0.5 to about 35 mg/kg/day, in single ordivided doses. For a 70 kg human, this would amount to about 0.0035 to2.5 g/day, preferably about 0.05 to about 2.5 g/day. In some instances,dosage levels below the lower limit of the aforesaid range may be morethan adequate, while in other cases still larger doses may be employedwithout causing any harmful side effect, provided that such larger dosesare first divided into several small doses for administration throughoutthe day. For further information on routes of administration and dosageregimes, see Chapter 25.3 in Volume 5 of Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press1990.

The size of the dose for therapeutic or prophylactic purposes of acompound of Formula I will naturally vary according to the nature andseverity of the conditions, the age and sex of the animal or patient andthe route of administration, according to well known principles ofmedicine.

In another embodiment of the invention, an article of manufacture, or“kit”, containing materials useful for the treatment of the disordersdescribed above is provided. In one embodiment, the kit comprises acontainer comprising a composition of Formula I or a pharmaceuticallyacceptable solvate or salt thereof. The kit may further comprise a labelor package insert on or associated with the container. Suitablecontainers include, for example, bottles, vials, syringes, blister pack,etc. The container may be formed from a variety of materials such asglass or plastic. The container holds a compound of Formula I or apharmaceutically acceptable solvate or salt thereof, or a formulationthereof which is effective for treating the condition and may have asterile access port (for example, the container may be an intravenoussolution bag or a vial having a stopper pierceable by a hypodermicinjection needle). The label or package insert indicates that thecomposition is used for treating the condition of choice, such ascancer. In one embodiment, the label or package inserts indicates thatthe composition comprising a compound of Formula I or a pharmaceuticallyacceptable solvate or salt thereof, can be used to treat a disorderresulting from abnormal cell growth. The label or package insert mayalso indicate that the composition can be used to treat other disorders.Alternatively, or additionally, the article of manufacture may furthercomprise a second container comprising a pharmaceutically acceptablebuffer, such as bacteriostatic water for injection (BWFI),phosphate-buffered saline, Ringer's solution and dextrose solution. Itmay further include other materials desirable from a commercial and userstandpoint, including other buffers, diluents, filters, needles, andsyringes.

The kit may further comprise directions for the administration of thecompound of Formula I or a pharmaceutically acceptable solvate or saltthereof, and, if present, the second pharmaceutical formulation. Forexample, if the kit comprises a first composition comprising a compoundof Formula I or a pharmaceutically acceptable solvate or salt thereof,and a second pharmaceutical formulation, the kit may further comprisedirections for the simultaneous, sequential or separate administrationof the first and second pharmaceutical compositions to a patient in needthereof.

In another embodiment, the kits are suitable for the delivery of solidoral forms of a compound of Formula I, or a pharmaceutically acceptablesolvate or salt thereof, such as tablets or capsules. Such a kitpreferably includes a number of unit dosages. Such kits can include acard having the dosages oriented in the order of their intended use. Anexample of such a kit is a “blister pack”. Blister packs are well knownin the packaging industry and are widely used for packagingpharmaceutical unit dosage forms. If desired, a memory aid can beprovided, for example in the form of numbers, letters, or other markingsor with a calendar insert, designating the days in the treatmentschedule in which the dosages can be administered.

According to one embodiment, an article of manufacture may comprise (a)a first container with a compound of Formula I or a pharmaceuticallyacceptable solvate or salt thereof, contained therein; and optionally(b) a second container with a second pharmaceutical formulationcontained therein, wherein the second pharmaceutical formulationcomprises a second compound with anti-hyperproliferative activity.Alternatively, or additionally, the article of manufacture may furthercomprise a third container comprising a pharmaceutically acceptablebuffer, such as bacteriostatic water for injection (BWFI),phosphate-buffered saline, Ringer's solution and dextrose solution. Itmay further include other materials desirable from a commercial and userstandpoint, including other buffers, diluents, filters, needles, andsyringes.

In certain other embodiments wherein the kit comprises a composition ofFormula I and a second therapeutic agent, the kit may comprise acontainer for containing the separate compositions such as a dividedbottle or a divided foil packet; however, the separate compositions mayalso be contained within a single, undivided container. Typically, thekit comprises directions for the administration of the separatecomponents. The kit form is particularly advantageous when the separatecomponents are preferably administered in different dosage forms (e.g.,oral and parenteral), are administered at different dosage intervals, orwhen titration of the individual components of the combination isdesired by the prescribing physician.

Accordingly this invention also provides a kit for treating an abnormalcell growth condition, wherein said kit comprises a) a firstpharmaceutical composition comprising a compound of this invention or apharmaceutically acceptable salt thereof; and b) instructions for use.

In certain embodiments, the kit further comprises (c) a secondpharmaceutical composition, wherein the second pharmaceuticalcomposition comprises a second compound having anti-hyperproliferativeactivity. In certain embodiment comprising a second pharmaceuticalcomposition, the kit further comprises instructions for thesimultaneous, sequential or separate administration of said first andsecond pharmaceutical compositions to a patient in need thereof. Incertain embodiments, said first and second pharmaceutical compositionsare contained in separate containers. In other embodiments, said firstand second pharmaceutical compositions are contained in the samecontainer.

In certain embodiments, this invention provides a kit for treating anabnormal cell growth condition such as hyperproliferative disorder or ahypoproliferative disorder. In other embodiments, this inventionprovides a kit for treating an abnormal cell growth condition such ascancer, autoimmune disease, arthritis, graft rejection, inflammatorybowel disease, or proliferation induced after a medical procedure. Inother embodiments, this invention provides a kit for treating a fungalor other eukaryote infection in a mammal.

Representative compounds of the present invention, which are encompassedby the present invention include, but are not limited to the compoundsof the examples and the salts, solvates, metabolites or prodrugsthereof. The examples presented below are intended to illustrateparticular embodiments of the invention, and are not intended to limitthe scope of the specification or the claims in any way.

EXAMPLES

In order to illustrate the invention, the following examples areincluded. However, it is to be understood that these examples do notlimit the invention and are only meant to suggest a method of practicingthe invention. Persons skilled in the art will recognize that thechemical reactions described may be readily adapted to prepare a numberof other KSP inhibitors of the invention, and alternative methods forpreparing the compounds of this invention are deemed to be within thescope of this invention. For example, the synthesis of non-exemplifiedcompounds according to the invention may be successfully performed bymodifications apparent to those skilled in the art, e.g., byappropriately protecting interfering groups, by utilizing other suitablereagents known in the art other than those described, and/or by makingroutine modifications of reaction conditions. Alternatively, otherreactions disclosed herein or known in the art will be recognized ashaving applicability for preparing other compounds of the invention.

In the examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius. Reagents were purchasedfrom commercial suppliers such as Aldrich Chemical Company, Lancaster,TCI or Maybridge, and were used without further purification unlessotherwise indicated. Tetrahydrofuran (THF), N,N-dimethylformamide (DMF),dichloromethane (DCM), toluene, dioxane and 1,2-dichloroethane (DCE)were purchased from Aldrich in Sure seal bottles and used as received.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heat dried.

Column chromatography was done on a Biotage system (Manufacturer: DyaxCorporation) having a silica gel column or on a silica SepPak cartridge(Waters).

¹H-NMR spectra were recorded on a Varian instrument operating at 400MHz. ¹H-NMR spectra were obtained as CDCl₃ solutions (reported in ppm),using chloroform as the reference standard (7.25 ppm). Other NMRsolvents were used as needed. When peak multiplicities are reported, thefollowing abbreviations are used: s (singlet), d (doublet), t (triplet),m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet oftriplets). Coupling constants, when given, are reported in Hertz (Hz).

Example 1

3-(5-(2,5-difluorophenyl)-3-(oxazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine

Step A: di-tert-butyl3-(5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylaminodicarboxylate:A mixture of 2,4-difluorobenzothiohydrazide (1.57 g, 8.32 mmol) anddi-tert-butyl 4-oxo-4-phenylbutylamino dicarboxylate (3.32 g, 9.15 mmol)in EtOH/DCM (20 mL/20 mL) was stirred at room temperature for 48 hours.The mixture was concentrated under reduced pressure and the residue waschromatographed (20:1 hexanes/EtOAc) to provide the product (3.12 g,70%).

Step B: di-tert-butyl3-(5-(2,5-difluorophenyl)-3-(1H-imidazole-1-carbonyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylaminodicarboxylate:A mixture of di-tert-butyl3-(5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylaminodi-carboxylate(0.49 g, 0.92 mmol) and carbonyldiimidazole (0.179 g, 1.11 mmol) in THF(9 mL) was heated to 70° C. for 16 hours. Two more equivalents of CDIwere added and the mixture was heated to 75° C. for 1 hour. The reactionmixture was partitioned between dichloromethane (25 mL) and 0.2 M HCl(35 mL). The aqueous layer was extracted with dichloromethane (25 mL)and the combined organics were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to provide the crude product (0.58g, 100%) as a brown oil.

Step C: di-tert-butyl 3-(5-(2,5-difluorophenyl)-3-((2,2-dimethoxyethyl)carbamoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylaminodicarboxylate:To a solution of di-tert-butyl3-(5-(2,5-difluorophenyl)-3-(1H-imidazole-1-carbonyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylaminodicarboxylate(0.289 g, 0.461 mmol) in acetonitrile (3 mL) was added iodomethane(0.288 mL, 4.61 mmol). After stirring at room temperature for 4 hours,another 5 equivalents of Mel were added, and then again at 20 hours, 24hours, and 28 hours (5 equivalents Mel at each time point). The mixturewas concentrated under reduced pressure and the residue was dissolved indichloromethane (5 mL). To this solution was added2,2-dimethoxyethanamine (0.121 mL, 1.11 mmol). After stirring at roomtemperature for 16 hours, water (30 mL) was added and the mixture wasextracted with dichloromethane (2×25 mL). The combined organics weredried over Na₂SO₄, filtered, and concentrated under reduced pressure toprovide the product (0.270 g, 88%) as a brown oil.

Step D: tert-butyl3-(5-(2,5-difluorophenyl)-3-((2-oxoethyl)carbamoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate:To a solution of di-tert-butyl3-(5-(2,5-difluorophenyl)-3-((2,2-dimethoxyethyl)carbamoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylaminodicarboxylate(0.258 g, 0.388 mmol) in THF/water (10 mL, 5:1) was addedp-toluenesulfonic acid (0.060 g, 0.345 mmol). After heating to 70° C.for 16 hours, the mixture was diluted with ethyl acetate (100 mL) andwashed with saturated NaHCO₃ (30 mL), brine (30 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to provide the crudeproduct (188 mg) as a brown film.

Step E:3-(5-(2,5-difluorophenyl)-3-(oxazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine:To a cooled (0° C.) solution of tert-butyl3-(5-(2,5-difluorophenyl)-3-((2-oxoethyl)carbamoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate(0.188 g, 0.363 mmol) in dichloromethane (15 mL) was addedtriphenylphosphine (0.475 g, 1.81 mmol) and 2,6-di-tert-butylpyridine(1.63 mL, 7.25 mmol) followed by 1,2-dibromo-1,1,2,2-tetrachloroethane(0.590 g, 1.81 mmol). After stirring at 0° C. for 45 minutes, a solutionof DBU (1.63 mL, 10.9 mmol) in acetonitrile (15 mL) was added. Themixture was slowly warmed to room temperature. After stirring for 36hours, the reaction mixture was concentrated under reduced pressure. Theresidue was dissolved in ethyl acetate (50 mL) and washed with 0.2 M HCl(30 mL). The aqueous layer was extracted with ethyl acetate (30 mL) andthe combined organics were dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was chromatographed (20% ethylacetate in hexanes) to provide the Boc-protected product. To thisproduct dissolved in dichloromethane (0.5 mL) was added TFA (50 μL).After stirring at 0° C. for 30 minutes and at room temperature for 30minutes, the mixture was concentrated under reduced pressure to providethe di-TFA salt product as pale yellow film. MS ESI (+) m/z 401 (M+1)detected; ¹H NMR (400 MHz, CDCl₃) δ 8.28 (br, 2H), 7.69 (m, 1H), 7.46(m, 2H), 7.33 (m, 3H), 7.22 (m, 1H), 7.07 (m, 2H), 6.89 (m, 1H), 3.05(m, 2H), 2.64 (m, 1H), 2.24 (m, 1H), 1.94 (m, 1H), 1.83 (m, 1H).

Example 2

3-(5-(2,5-difluorophenyl)-2-phenyl-3-(thiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine

Step A: di-tert-butyl3-(3-carbamothioyl-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylaminodicarboxylate:A mixture of di-tert-butyl3-(5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylaminodicarboxylate(0.029 g, 0.054 mmol) and di(1H-imidazol-1-yl)methanethione (0.019 g,0.11 mmol) in DMF (0.5 mL) was heated to 95° C. for 17 hours to providea crude mixture containing the desired di-tert-butyl3-(5-(2,5-difluorophenyl)-3-(1H-imidazole-1-carbonothioyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylaminodicarboxylate.To this mixture was added ammonia (0.1 mL of 0.5 M solution in dioxane).After heating to 40° C. for 13 hours, concentrated aqueous ammoniumhydroxide (5 drops) was added. After stirring at room temperature for 16hours, the mixture was diluted with ethyl acetate (70 mL) and washedwith brine (30 mL). The organic layer was dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was chromatographed(15% ethyl acetate in hexanes) to afford the product (5.8 mg) as a brownfilm.

Step B:3-(5-(2,5-difluorophenyl)-2-phenyl-3-(thiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine:To a solution of di-tert-butyl3-(3-carbamothioyl-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylaminodicarboxylate(0.006 g, 0.010 mmol) in EtOH (1 mL) was added 2-chloroacetaldehyde (50%aqueous solution, 0.015 mL, 0.12 mmol). After heating to 80° C. for 16hours, another 15 μL of the 2-chloroacetaldehyde solution was addedfollowed by DIEA (0.041 mL, 0.23 mmol). After heating to 90° C. for 7hours, the mixture was partitioned between ethyl acetate (25 mL) andsaturated NaHCO₃ (30 mL). The aqueous layer was extracted with ethylacetate (2×25 mL). The combined organics were washed with brine (30 mL),dried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was chromatographed (10% ethyl acetate in hexanes) toprovide 2.5 mg of the mono Boc-protected product as a yellow film. Tothis product dissolved in dichloromethane (0.5 mL) and cooled to 0° C.was added TFA (50 μL). After stirring at 0° C. for 2 hours, the mixturewas concentrated under reduced pressure to provide the TFA salt productas a pale yellow film. MS ESI (+) m/z 417 (M+1) detected; ¹H NMR (400MHz, CDCl₃) δ 8.56 (br, 1H), 7.59 (m, 1H), 7.38 (d, 2H, J=7 Hz), 7.31(m, 3H), 7.06 (m, 4H), 6.65 (d, 1H, J=4 Hz), 3.36 (m, 1H), 3.00 (m, 2H),2.60 (m, 1H), 2.21 (m, 1H), 1.83 (m, 1H).

The following were prepared similarly using the appropriate2-haloketone:

Example 2A

3-(5-(2,5-difluorophenyl)-3-(4-methylthiazol-2-yl-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine

MS ESI (+) m/z 431 (M+1) detected; ¹H NMR (400 MHz, CDCl3) δ 8.58 (br,3H), 7.67 (m, 2H), 7.41 (m, 3H), 7.07 (m, 2H), 6.19 (m, 1H), 3.71 (s,3H), 3.42 (m, 1H), 3.10 (m, 1H), 2.68 (m, 1H), 2.32 (m, 2H), 1.32 (m,1H).

Example 2B

3-(5-(2,5-difluorophenyl)-3-(4-ethylthiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine

MS ESI (+) m/z 445 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 8.58 (br,3H), 7.71 (m, 2H), 7.43 (m, 3H), 7.09 (m, 2H), 6.20 (m, 1H), 3.71 (m,2H), 3.40 (m, 1H), 3.09 (m, 1H), 2.72 (m, 3H), 2.10 (m, 1H), 1.11 (m,3H).

Example 3

5-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-3,4-dihydropyrrol-2-one

To a solution of 5-ethoxy-3,4-dihydropyrrol-2-one (0.16 g, 1.3 mmol) inIPA/THF (2 mL/2 mL) was added tert-butyl3-(5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate(0.052 g, 0.13 mmol) and acetic acid (0.1 mL). After heating to 90° C.for 5 hours in a sealed tube, the mixture was concentrated under reducedpressure. The residue was chromatographed (1:6 to 1:4 ethylacetate/hexanes) to provide the Boc-protected product (0.026 g, 42%). Tothis product dissolved in dichloromethane (1 mL) was added TFA (1 mL).After stirring at room temperature for 30 minutes, the mixture wasconcentrated under high vacuum for 16 hours to provide the final productas the di-TFA salt. MS ESI (+) m/z 397 (M+1) detected; ¹H NMR (400 MHz,CDCl₃) δ 8.11 (br, 2H), 7.44 (m, 5H), 7.34 (m, 3H), 7.22 (m, 1H), 3.57(m, 1H), 3.29 (m, 1H), 3.20 (m, 2H), 3.05 (m, 1H), 2.57 (m, 1H), 2.46(m, 2H), 2.13 (m, 1H), 1.78 (m, 1H).

Example 4

3-(5-(2,5-difluorophenyl)-3-(4,5-dihydrothiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine

To a solution of di-tert-butyl3-(5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylaminodicarboxylate(0.182 g, 0.34 mmol) in THF (3 mL) was addeddi(1H-imidazol-1-yl)methanethione (0.091 g, 0.51 mmol). After heating to70° C. for 2 hours, the mixture was cooled to room temperature and2-bromoethanamine hydrobromide (0.69 g, 3.4 mmol) followed by aceticacid (0.061 g, 1.0 mmol) were added. After heating to 88° C. for 8hours, the mixture was cooled to room temperature and chromatographed(1:20 to 1:10 ethyl acetate/hexanes) to provide the Boc-protectedproduct (21 mg, 10%). To this product was added formic acid (1 mL). Themixture was stirred at room temperature for 1 hour and concentratedunder reduced pressure to provide the final product as the formate salt.MS ESI (+) m/z 419 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 8.40 (br,1H), 7.54 (m 1H), 7.35 (m, 4H), 7.27 (m, 2H), 7.03 (m, 2H), 4.08 (m,1H), 3.89 (m, 1H), 3.22 (m, 3H), 2.94 (m, 2H), 2.47 (m, 1H), 2.14 (m,1H), 1.80 (m, 1H).

Example 5

3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine

Step A:(5-(2,5-difluorophenyl)-2-(3-di-tert-butoxycarbonylaminopropyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(1H-3-methylimidazolium-1-yl)methanoneiodide: To a solution of di-tert-butyl3-(5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylaminodicarboxylate(0.335 g, 0.628 mmol) in THF (3 mL) was addeddi(1H-imidazol-1-yl)methanone (0.122 g, 0.753 mmol). After heating to70° C. for 2 hours, the mixture was cooled to room temperature andconcentrated under reduced pressure. The residue was dissolved indichloromethane (5 mL) and washed with water (2×3 mL), dried overNa₂SO₄, and concentrated under reduced pressure. This residue wasdissolved in acetonitrile (2 mL) and treated with iodomethane (0.446 g,3.14 mmol) for 24 hours. The mixture was then concentrated under reducedpressure to afford the crude product.

Step B:N′-acetyl-2-(3-di-tert-butoxycarbonylaminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbohydrazide:To a solution of(5-(2,5-difluorophenyl)-2-(3-di-tert-butoxycarbonylaminopropyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(1H-3-methylimidazolium-1-yl)methanoneiodide (0.211 g, 0.274 mmol) and triethylamine (0.069 g, 0.0685 mmol) indichloromethane (3 mL) was added acetohydrazide (0.041 g, 0.548 mmol).After stirring for 30 minutes, the mixture was partitioned betweendichloromethane (10 mL) and saturated NaHCO₃ (5 mL). The aqueous layerwas extracted with dichloromethane (10 mL). The combined organics werewashed with brine (10 mL), dried over Na₂SO₄, and concentrated underreduced pressure. The residue was chromatographed (10:1 to 4:1hexanes/ethyl acetate) to provide the final product (0.123 g, 71%).

Step C:3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine:To a solution ofN′-acetyl-2-(3-di-tert-butoxycarbonylaminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbohydrazide(0.052 g, 0.082 mmol) and DIEA (0.11 g, 0.82 mmol) in dichloroethane (2mL) was added POCl₃ (0.063 g, 0.41 mmol). After stirring at roomtemperature for 30 minutes, the mixture was partitioned betweendichloromethane (10 mL) and saturated NaHCO₃ (5 mL). The aqueous layerwas extracted with dichloromethane and the combined organics were washedwith brine (10 mL), dried over Na₂SO₄, and concentrated under reducedpressure. The residue was chromatographed (20:1 to 10:1 hexanes/ethylacetate) to provide the Boc-protected product (0.033 g, 65%). To thisproduct was added formic acid (1 mL). After stirring at room temperaturefor 45 minutes, the mixture was concentrated under reduced pressure toprovide the final product as the formate salt. MS ESI (+) m/z 416 (M+1)detected; ¹H NMR (400 MHz, CDCl₃) δ 8.88 (br, 2H), 7.64 (m, 1H), 7.47(d, 2H, J=8 Hz), 7.31 (m, 3H), 7.11 (m, 2H), 3.27 (m, 1H), 3.02 (m, 2H),2.51 (m, 1H), 2.39 (s, 3H), 2.15 (m, 1H), 1.74 (m, 1H).

The following were prepared similarly using the appropriate hydrazides:

Example 5A

3-(5-(2,5-difluorophenyl)-3-(5-ethyl-1,3,4-oxadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine

MS ESI (+) m/z 430 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 8.30 (br,1H), 7.65 (m, 1H), 7.49 (d, 2H, J=8 Hz), 7.45 (br, 1H), 7.30 (m, 2H),7.10 (m, 2H), 3.29 (m, 1H), 3.01 (m, 2H), 2.73 (q, 2H, J=7 Hz), 2.52 (m,1H), 2.15 (m, 1H), 1.76 (m, 1H), 1.27 (t, 3H, J=7 Hz).

Example 5B

Ethyl2-(5-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-1,3,4-oxadiazol-2-yl)acetate

MS ESI (+) m/z 488 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 8.38 (s,1H), 7.66 (m, 1H), 7.50 (d, 2H), 7.31 (m, 3H), 7.09 (m, 2H), 6.87 (br,2H), 4.18 (q, 2H), 3.82 (d, 2H), 3.26 (m, 1H), 2.99 (m, 2H), 2.58 (m,1H), 2.15 (m, 1H), 1.73 (m, 1H), 1.25 (t, 3H).

Example 6

5-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-N-ethyl-1,3,4-oxadiazol-2-amine

Step A:1-(2-(3-di-tert-butoxycarbonylaminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole-3-carbonyl)-4-ethylthiosemicarbazide:To a stirred solution of tert-butyl3-(5-(2,5-difluorophenyl)-3-(1H-3-methylimidazolium-1-carbonyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamateiodide (0.396 g, 0.591 mmol) in dichloromethane (4 mL) under N₂ wasadded triethylamine (0.206 mL, 1.48 mmol) followed by4-ethylthiosemicarbazide (0.141 g, 1.18 mmol). After stirring for 30minutes, the mixture was diluted with dichloromethane and saturatedNaHCO₃. The aqueous layer was extracted with dichloromethane and thecombined organics were washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was chromatographed(2:1 hexanes/ethyl acetate) to provide the product (0.167 g, 49%) as awhite foam.

Step B:5-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-N-ethyl-1,3,4-oxadiazol-2-amine:To a solution of1-(2-(3-di-tert-butoxycarbonylaminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole-3-carbonyl)-4-ethylthiosemicarbazide(0.033 g, 0.057 mmol) in THF (1 mL) under N₂, was added triethylamine(0.0199 mL, 0.143 mmol) followed by EDCI (0.022 g, 0.114 mmol). Afterheating the mixture to 50° C. for 16 hours, the mixture was cooled toroom temperature and diluted with ethyl acetate. The organic layer waswashed with saturated NH₄Cl (2×), saturated NaHCO₃, and brine. Thesolution was dried over Na₂SO₄ and concentrated under reduced pressure.The residue was chromatographed (1:1 hexanes/ethyl acetate) to providethe Boc-protected product (0.021 g, 68%) as yellow solid. To thisproduct was added formic acid (0.5 mL). After stirring at roomtemperature for 90 minutes, the mixture was concentrated under reducedpressure, sonicated with pentane, and dried in vacuo to provide thefinal product (0.017 g, 90%) as the formate salt. MS APCI (+) m/z 445(M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.86 (br, 2H), 7.58 (m, 1H),7.48 (d, 2H), 7.28 (m, 3H), 7.06 (m, 2H), 6.00 (br, 1H), 3.18 (m, 3H),3.01 (m, 1H), 2.91 (m, 1H), 2.43 (m, 1H), 2.12 (m, 1H), 1.81 (m, 1H),1.11 (t, 3H).

Example 7

2-(5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5-methyl-1,3,4-oxadiazole

Step A: 2-(methoxymethoxy)-1-phenylethanone: To a cooled (0° C.)solution of 2-hydroxy-1-phenylethanone (1.0 g, 7.3 mmol) in anhydrousDMF (50 mL) was added lithium hydride (74 mg, 95%, 8.8 mmol). Afterstirring the brown mixture for 30 minutes, MOM-Cl (0.73 mL, 9.5 mmol)was added slowly via syringe. The mixture warmed slowly to roomtemperature and stirred for 16 hours. The mixture was treated with NH₄Cl(100 mL) and then extracted with ethyl acetate (3×50 mL). The combinedorganics were washed with water (6×50 mL) and brine (50 mL) then driedover Na₂SO₄ and concentrated under reduced pressure. The brown residuewas chromatographed (9:1 to 4:1 hexanes/ethyl acetate) to provide theproduct (0.60 g, 45%) as a colorless oil.

Step B:5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole:To a solution of 2-(methoxymethoxy)-1-phenylethanone (600 mg, 3.33 mmol)in ethanol/dichloromethane (12 mL, 3:1) was added2,5-difluorobenzothiohydrazide (627 mg, 3.33 mmol). After stirring atroom temperature for 16 hours, the mixture was concentrated underreduced pressure and chromatographed (9:1 hexanes/ethyl acetate) toafford the product (734 mg, 63%) as a yellow oil.

Step C:(5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(1H-3-methylimidazolium-1-yl)methanoneiodide: To a solution of5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole(0.234 g, 0.668 mmol) in THF (3 mL) was addeddi(1H-imidazol-1-yl)methanone (0.162 g, 1.00 mmol). After heating to 70°C. for 2 hours, the mixture was cooled to room temperature, concentratedunder reduced pressure and dissolved in dichloromethane (5 mL). Thesolution was washed with water (2×3 mL), dried over Na₂SO₄, concentratedunder reduced pressure and dissolved in acetonitrile (2 mL). Iodomethane(0.474 g, 3.34 mmol) was added and the mixture was stirred at roomtemperature for 24 hours. The mixture was concentrated under reducedpressure to provide the crude product.

Step D:N′-acetyl-5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbohydrazide:To a solution of(5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(1H-3-methylimidazolium-1-yl)methanoneiodide (0.392 g, 0.668 mmol) in dichloromethane (4 mL) was addedacetohydrazide (0.099 g, 1.34 mmol). After stirring for 1 hour, themixture was concentrated under reduced pressure and chromatographed(10:1 hexanes/ethyl acetate) to provide the product (0.221 g, 73%).

Step E:2-(5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5-methyl-1,3,4-oxadiazole:To a mixture ofN′-acetyl-5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbohydrazide(0.221 g, 0.491 mmol) and DIEA (0.634 g, 4.91 mmol) in dichloroethane(10 mL) was added POCl₃ (0.376 g, 2.45 mmol). After stirring for 30minutes, the mixture was partitioned between dichloromethane (10 mL) andsaturated NaHCO₃ (5 mL). The organic layer was extracted withdichloromethane (10 mL). The combined organic layers were washed withbrine (10 mL), dried over Na₂SO₄, and chromatographed (20:1 to 10:1hexanes/ethyl acetate) to provide the final product (0.080 g, 38%). MSESI (+) m/z 433 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.68 (m, 1H),7.54 (d, 2H, J=7 Hz), 7.35 (m, 3H), 7.10 (m, 2H), 4.90 (d, 1H, J=11 Hz),4.74 (m, 2H), 4.52 (d, 1H, J=11 Hz), 3.37 (s, 3H), 2.44 (s, 3H).

Example 8

3-(5-(2,5-difluorophenyl)-2-phenyl-3-(1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine

Step A:2-(3-tert-butoxycarbonylaminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothiohydrazide:To a solution of tert-butyl3-(5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate(0.123 g, 0.284 mmol) in THF (2 mL) was addeddi(1H-imidazol-1-yl)methanethione (0.061 g, 0.340 mmol). After heatingto 70° C. for 2 hours, the reaction mixture was cooled to roomtemperature and treated with hydrazine (0.027 g, 0.851 mmol). Afterstirring for 1 hour, the mixture was concentrated under reduced pressureand chromatographed (10:1 hexanes/ethyl acetate) to provide the product(0.036 g, 25%).

Step B:3-(5-(2,5-difluorophenyl)-2-phenyl-3-(1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine:To a solution of2-(3-tert-butoxycarbonylaminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothiohydrazide(0.018 g, 0.035 mmol) in trimethoxymethane (1 mL) was added4-methylbenzenesulfonic acid (0.6 mg, 0.0035 mmol). After heating to 60°C. for 1 hour, the mixture was cooled to room temperature andchromatographed (10:1 hexanes/ethyl acetate) to provide theBoc-protected product (5 mg, 27%). To this product was added formic acid(1 mL). After stirring at room temperature for 30 minutes, the reactionmixture was concentrated under reduced pressure to provide the finalproduct as the formate salt. MS ESI (+) m/z 418 (M+1) detected; ¹H NMR(400 MHz, CDCl₃) δ 8.49 (s, 1H), 8.30 (s, 1H), 7.56 (m, 1H), 7.45 (d,2H), 7.41 (br, 1H), 7.31 (m, 2H), 7.24 (m, 1H), 7.10 (m, 2H), 3.52 (m,1H), 2.94 (m, 2H), 2.52 (m, 1H), 2.13 (m, 1H), 1.67 (m, 1H).

Example 9

3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine

Step A:N′-acetyl-2-(3-tert-butoxycarbonylaminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothiohydrazide:To a solution of2-(3-tert-butoxycarbonylaminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothiohydrazide(0.016 g, 0.032 mmol) in dichloromethane (1 mL) was added aceticanhydride (0.032 g, 0.32 mmol). After stirring for 1 hour at roomtemperature, the reaction mixture was concentrated under reducedpressure and chromatographed (10:1 hexanes/ethyl acetate) to provide theproduct.

Step B:3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine:To a solution ofN′-acetyl-2-(3-tert-butoxycarbonylaminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothiohydrazide(0.008 g, 0.015 mmol) in dichloroethane (1 mL) was added POCl₃ (0.011 g,0.073 mmol) and DIEA (0.019 g, 0.15 mmol). After stirring at roomtemperature for 30 minutes, the mixture was partitioned betweensaturated NaHCO₃ (2 mL) and dichloromethane (5 mL). The organic layerwas dried over Na₂SO₄, concentrated under reduced pressure andchromatographed (10:1 hexanes/ethyl acetate) to provide theBoc-protected product (2 mg, 26%). To this product was added formic acid(1 mL). After stirring for 30 minutes, the mixture was concentratedunder reduced pressure to provide the final product as the formate salt.MS ESI (+) m/z 432 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 8.20 (br,2H), 7.53 (m, 1H), 7.44 (d, 2H), 7.32 (m, 3H), 7.11 (m, 2H), 3.53 (m,1H), 3.03 (m, 1H), 2.97 (m, 1H), 2.52 (s, 3H), 2.45 (m, 1H), 2.19 (m,1H), 1.75 (m, 1H).

Example 10

3-(5-(2,5-difluorophenyl)-3-(3-methyl-1,2,4-oxadiazol-5-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine

Step A: di-tert-butyl3-(5-(2,5-difluorophenyl)-3-((1-(acetoxyimino)ethyl)carbamoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylaminodicarboxylate:To a solution of(5-(2,5-difluorophenyl)-2-(3-di-tert-butoxycarbonylaminopropyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(1H-3-methylimidazolium-1-yl)methanoneiodide (0.101 g, 0.131 mmol) dissolved in dichloromethane (2 mL) wasadded N′-hydroxyacetamidine (0.009 g, 0.131 mmol) followed bytriethylamine (0.016 g, 0.157 mmol). After stirring at room temperaturefor 1 hour, the mixture was chromatographed (10:1 hexanes/ethyl acetate)to provide the oxime product. This product was dissolved indichloromethane (1 mL) and treated with acetic anhydride (0.080 g, 0.787mmol). After stirring at room temperature for 24 hours, the reactionmixture was concentrated under reduced pressure to provide the crudeproduct.

Step B:3-(5-(2,5-difluorophenyl)-3-(3-methyl-1,2,4-oxadiazol-5-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine:di-tert-butyl3-(5-(2,5-difluorophenyl)-3-((1-(acetoxyimino)ethyl)carbamoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylaminodicarboxylatewas heated in pyridine (1 mL) in a sealed tube to 80° C. for 12 hours.The reaction mixture was cooled to room temperature and diluted withethyl acetate (10 mL) and HCl (5 mL of 1M solution). The organic layerwas dried over Na₂SO₄ and chromatographed (20:1 to 10:1 hexanes/ethylacetate) to provide the Boc-protected product (2 mg, 27%). To thisproduct was added formic acid (1 mL). After stirring at room temperaturefor 30 minutes, the reaction mixture was concentrated under reducedpressure to provide the final product as the formate salt. MS ESI (+)m/z 416 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 8.19 (br, 1H), 7.71(m, 1H), 7.43 (d, 2H), 7.33 (m, 3H), 7.10 (m, 2H), 3.19 (m, 1H), 3.03(m, 2H), 2.64 (m, 1H), 2.21 (m, 1H), 2.17 (s, 3H), 1.73 (m, 1H).

Example 11

3-(5-(2,5-difluorophenyl)-2-phenyl-3-(5-phenyl-4H-1,2,4-triazol-3-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine

Step A: tert-butyl3-(3-(benzoylcarbamothioyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate:To a solution of tert-butyl3-(5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate(1.60 g, 3.69 mmol) in THF (37 mL) was added benzoyl isothiocyanate(0.595 mL, 4.43 mmol). After heating to reflux for 5 hours and to 60° C.for 16 hours, the reaction mixture was concentrated under reducedpressure. The residue was chromatographed (30% ethyl acetate in hexanes)to provide the product (1.84 g, 84%) as an orange-yellow foam.

Step B: methylN-benzoyl-2-(3-(tert-butoxycarbonyl)propyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbthioimidate:To a cooled (0° C.) solution of tert-butyl3-(3-(benzoylcarbamothioyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate(0.022 g, 0.037 mmol) in THF (0.4 mL) was added sodium carbonate (0.022g, 0.208 mmol) followed by iodomethane (0.006 mL, 0.096 mmol). Afterstirring at room temperature for 1 hour, more iodomethane (25 μL, 11equiv.) was added to the mixture. After stirring at room temperature for15 hours, the mixture was diluted with saturated NaHCO₃ and extractedwith ethyl acetate (3×25 mL). The combined organics were washed withbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure to provide the crude product as a brown film.

Step C:3-(5-(2,5-difluorophenyl)-2-phenyl-3-(5-phenyl-4H-1,2,4-triazol-3-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine:To a cooled (0° C.) solution of methylN-benzoyl-2-(3-(tert-butoxycarbonyl)propyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbthioimidate(0.011 g, 0.018 mmol) in ethanol (0.5 mL) was added hydrazine (0.007 mL,0.223 mmol). The ice bath was removed and the mixture stirred at roomtemperature for 1 hour. After concentrating the mixture under reducedpressure, the residue was chromatographed (20% ethyl acetate in hexanes)to provide the Boc-protected product (0.010 g, 98%). To this product wasadded HCl (0.5 mL of 4.0 M solution, 2.0 mmol). After stirring at 0° C.for 2 hours and room temperature for 1 hour, the reaction mixture wasconcentrated under reduced pressure, washed with ether, filtered anddried to provide the final product as the di-HCl salt. MS ESI (+) m/z477 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.95 (m, 3H), 7.52 (m,5H), 7.34 (m, 3H), 7.14 (m, 2H), 3.45 (m, 1H), 3.14 (m, 1H), 3.05 (m,1H), 2.64 (m, 1H), 2.30 (m, 1H), 1.92 (m, 1H).

The compounds of Examples 12-15 were prepared according to theabove-described methods, using the appropriate starting materials.

Example 12

3-(5-(2,5-difluorophenyl)-3-(1-methyl-5-phenyl-H-1,2,4-triazol-3-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine

MS ESI (+) m/z 491 (M+1) detected; ¹H NMR (400 MHz, 19:1 CDCl₃:CD₃OD) δ7.93 (m, 1H), 7.78-7.71 (m, 2H), 7.68-7.56 (m, 5H), 7.42 (t, 2H, J=7Hz), 7.35 (m, 1H), 7.15-7.11 (m, 2H), 3.43 (m, 1H), 3.37 (s, 3H),3.21-3.04 (m, 2H), 2.57 (m, 1H), 2.28 (m, 1H), 2.02 (m, 1H).

Example 13

3-(5-(2,5-difluorophenyl)-2-phenyl-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine

MS ESI (+) m/z 485 (M+1) detected; ¹H NMR (400 MHz, CD₃OD) δ 7.67 (m,1H), 7.54 (m, 2H), 7.42 (m, 2H), 7.33 (m, 3H), 3.49 (m, 1H), 3.09 (m,2H), 2.79 (m, 4H), 2.27 (m, 1H), 1.74 (m, 1H).

Example 14

3-(5-(2,5-difluorophenyl)-2-(4-fluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine

MS ESI (+) m/z 522 (M-17 [NH₃]) detected; ¹H NMR (400 MHz, CDCl₃) δ 8.65(s, 3H), 7.68 (m, 2H), 7.54 (m, 1H), 7.16 (m, 2H), 7.08 (t, 2H, J=8.2Hz), 3.70 (m, 1H), 3.25 (s, 1H), 3.04 (s, 1H), 2.93 (2, 3H), 2.43 (t,1H, J=11.7 Hz), 2.22 (s, 1H), 2.02 (s, 1H).

Example 15

3-(5-(2,5-difluorophenyl)-2-(3-fluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine

MS ESI (+) m/z 522 (M-17 [NH₃]) detected; ¹H NMR (400 MHz, CD₃OD) δ 7.61(m, 1H), 7.41 (m, 1H), 7.29 (m, 4H), 7.08 (m, 1H), 3.43 (m, 1H), 3.08(m, 2H), 2.69 (m, 1H), 2.59 (s, 3H), 2.32 (m, 1H), 1.76 (m, 1H).

Example 16

3-(5-(2,5-difluorophenyl-3-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine

Step A: Preparation ofN-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole-3-carbonothioyl)benzamide:To a solution of2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole(1.00 g, 2.79 mmol) in 20 mL of anhydrous THF was added benzoylisothiocyanate (0.45 mL, 3.34 mmol). The reaction mixture was stirredovernight at reflux, then cooled and concentrated in vacuo. The residuewas purified by flash column chromatography (5-35% ethylacetate/hexanes) to afford the desired product as a yellow gum (1.45 g,54%).

Step B: Preparation of2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothioamide:To a solution ofN-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole-3-carbonothioyl)benzamide(0.737 g, 1.41 mmol) in 20 mL of anhydrous THF was added hydrazine(0.088 mL, 2.82 mmol). The reaction mixture was stirred at roomtemperature for 3 hours, and then concentrated in vacuo. The residue waspurified by flash column chromatography (10-20% ethyl acetate/hexanes)to afford the desired product as a pale yellow foam, 0.504 g, 85%.

Step C: Preparation of tert-butyl2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate: To a solution of2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothioamide(0.300 g, 0.717 mmol) in 10 mL of ethanol was added tert-butyl3-bromo-4-oxopiperidine-1-carboxylate (0.239 g, 0.860 mmol) followed byDIEA (0.25 mL, 1.43 mmol). The mixture was allowed to stir overnight atreflux then treated with tert-butyl3-bromo-4-oxopiperidine-1-carboxylate (100 mg) and stirred at reflux fora further 3 hrs. The cooled mixture was partitioned between saturatedNaHCO₃ solution (30 mL) and EtOAc (30 mL) and the aqueous layer wasextracted with EtOAc (2×20 mL). The combined organic phases were washedwith brine (20 mL) dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography (5-10% ethylacetate/hexanes) to afford the desired product as a bright yellow foam(0.313 g, 73%).

Step D: Preparation of2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine:To a solution of tert-butyl2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(0.313 g, 0.524 mmol) in 10.0 mL of DCM at 0° C. was added TFA (1 mL).The mixture was stirred for 1 hour at 0° C. then at room temperature for1 hour. The reaction was then concentrated to dryness and partitionedbetween EtOAc (30 mL) and saturated NaHCO₃ solution (30 mL). The aqueouslayer was extracted with EtOAc (2×20 mL) and the combined organic phaseswere washed with brine (20 mL), dried over Na₂SO₄ and concentrated invacuo to afford the desired product as a yellow gum (0.251 g, 96%).

Step E: Preparation of2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine.To a solution of2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine(0.050 g, 0.100 mmol) in 1 mL DCE was added formaldehyde (0.033 g, 37 wt% in water, 0.401 mmol) followed by sodium triacetoxyborohydride (0.023g, 0.110 mmol). The resulting suspension was stirred vigorously at roomtemperature overnight then was treated with saturated Na₂CO₃ solution(10 mL) and stirred for 10 minutes. The mixture was extracted with EtOAc(3×10 mL) and the combined organic phases were washed with brine (10mL), dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography (0-3% MeOH/DCM) to afford thedesired product as a yellow foam (0.046 g, 89%).

Step F: Preparation of3-(5-(2,5-difluorophenyl)-3-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine.To a solution of2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine(0.046 g, 0.090 mmol) in 2 mL of methanol was added 1N HCl/MeOH (0.27mL, 0.27 mmol) followed by 10% Pd/C (10 mg). The mixture washydrogenated under a balloon atmosphere for 1 hour then filtered throughGF paper and the filtrate concentrated in vacuo. The residue wastriturated with diethyl ether, filtered, washed with ether and dried invacuo to afford the desired product as a bright yellow solid (0.027 g,50%). MS ESI (+) m/z 486 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.59(m, 1H), 7.45 (d, 2H, J=7.6 Hz), 7.32 (m, 2H), 7.26 (m, 1H), 7.06 (m,2H), 3.50 (m, 2H), 3.43 (m, 1H), 2.77 (t, 2H, J=6.9 Hz), 2.68 (m, 2H),2.56 (m, 2H), 2.46 (s, 3H), 2.41 (m, 1H), 1.99 (m, 1H), 1.55 (m, 1H)ppm.

Example 17

3-(5-(2,5-difluorophenyl)-2-phenyl-3-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine

To a solution of2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine(prepared as in Example 16, Steps A-D) (0.050 g, 0.100 mmol) in 2 mL ofmethanol was added 1N HCl/MeOH (0.30 mL, 0.30 mmol) followed by 10% Pd/C(10 mg). The mixture was hydrogenated under a balloon atmosphere for 1hour then filtered through GF paper and the filtrate concentrated invacuo. The residue was triturated with diethyl ether, filtered, washedwith ether and dried in vacuo to afford the desired product as a brightyellow solid, 0.018 g, 31%. MS ESI (+) m/z 472 (M+1) detected; ¹H NMR(400 MHz, CDCl₃) δ 7.59 (m, 1H), 7.46 (m, 2H), 7.33 (m, 3H), 7.05 (m,2H), 3.88 (m, 2H), 3.46 (m, 1H), 3.06 (m, 2H), 2.79 (m, 2H), 2.44 (m,3H), 2.01 (m, 1H), 1.57 (m, 1H) ppm.

Example 18

2-(5-(2,5-difluorophenyl)-2-methyl-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5-methyl-1,3,4-thiadiazole

Step A: Preparation of5-(2,5-difluorophenyl)-2-methyl-2-phenyl-2,3-dihydro-1,3,4-thiadiazole.To a solution of acetophenone (0.600 g, 5.00 mmol) in 20 mL of a 3:1EtOH/DCM mixture was added 2,5-difluorobenzothiohydrazide (0.941 g, 5.00mmol). The reaction was allowed to stir overnight at room temperature.The reaction was then heated to 45° C., for 14 hours. The reactionmixture was then concentrated in vacuo, and the residue was loadeddirectly to Biotage (45), followed by flash column chromatography (20%ethyl acetate/hexanes), yielding 5-(2,5-the desired product (1.021 g,70% yield) as a yellow semi-solid.

Step B: Preparation of5-(2,5-difluorophenyl)-2-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothiohydrazide.5-(2,5-difluorophenyl)-2-methyl-2-phenyl-2,3-dihydro-1,3,4-thiadiazole(0.290 g, 1.00 mmol) was weighed into a 25 mL flask, and suspended in 10mL of anhydrous THF, followed by addition of thiocarbonyldiimidazole(0.196 g, 1.10 mmol). The reaction was then heated to reflux for 3hours, at which time all starting material was consumed. The reactionwas cooled to room temperature, followed by addition of hydrazine (0.156mL, 5.00 mmol). Following 4 hours at room temperature, all intermediatewas consumed by LC-MS. The reaction was then concentrated, then loadedto Biotage-(45) followed by flash column chromatography (10-50% ethylacetate/hexanes), affording the desired product (80% purity; 0.268 g,74%).

Step C: Preparation of2-(5-(2,5-difluorophenyl)-2-methyl-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5-methyl-1,3,4-thiadiazole.5-(2,5-difluorophenyl)-2-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothiohydrazide(0.268 g, 0.735 mmol) was weighed into a 25 mL 1 neck flask, andsuspended in 9.0 mL of trimethylorthoacetate (0.088 g, 0.74 mmol).P-toluenesulfonic acid hydrate (0.0028 g, 0.015 mmol) was then added,and the reaction heated to 80° C. for 1 hour. The reaction was thenconcentrated in vacuo, and then purified by flash column chromatography(20-50% ethyl acetate/hexanes) yielding 0.201 g, 70% of the desiredproduct as a white solid. MS ESI (+) m/z 389 (M+1) detected; ¹H NMR (400MHz, CDCl₃) δ 7.56 (m, 2H), 7.34 (m, 2H), 7.27 (m, 2H), 7.08 (m, 2H),2.59 (s, 3H), 2.56 (s, 3H).

Example 19

3-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)phenol

Step A: Preparation of tert-butyl3-(2-(3-(tert-butyldimethylsilyloxy)phenyl)-5-(2,5-difluorophenyl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate.To a solution of tert-butyl4-(3-(tert-butyldimethylsilyloxy)phenyl)-4-oxobutylcarbamate (1.400 g,3.55 mmol) in 20 mL of a 3:1 EtOH/DCM mixture was added2,5-difluorobenzothiohydrazide (0.704 g, 3.74 mmol). The reaction wasstirred overnight at room temperature, then heated to 45° C. for 10hours. The reaction mixture was then concentrated in vacuo, loadeddirectly to Biotage (45), followed by flash column chromatography(20-50% ethyl acetate/hexanes), yielding the desired product as a yellowsemi-solid (1.742 g, 82%).

Step B: Preparation of tert-butyl3-(2-(3-(tert-butyldimethylsilyloxy)phenyl)-5-(2,5-difluorophenyl)-3-(hydrazinecarbonothioyl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl-carbamate.Tert-butyl3-(2-(3-(tert-butyldimethylsilyloxy)phenyl)-5-(2,5-difluorophenyl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate(0.845 g, 1.50 mmol) was weighed into a 25 mL flask and suspended in 10mL of anhydrous THF, followed by addition of thiocarbonyldiimidazole(0.294 g, 1.65 mmol). The reaction mixture was then heated to reflux for3 hours. The reaction was cooled to room temperature, and then hydrazine(0.235 mL 7.50 mmol) was added and the reaction mixture was stirred for4 hours at room temperature. The reaction mixture was concentrated, andthe residue was loaded onto Biotage (flash column chromatography 10-50%ethyl acetate/hexanes) to provide 143 mg (80% purity) of the desiredproduct.

Step C: Preparation of tert-butyl3-(2-(3-(tert-butyldimethylsilyloxy)phenyl)-5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate.Tert-butyl3-(2-(3-(tert-butyldimethylsilyloxy)phenyl)-5-(2,5-difluorophenyl)-3-(hydrazinecarbonothioyl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate(100 mg, 0.157 mmol) was weighed into a 25 mL flask and suspended in 5.0mL of 1,1,1-trimethoxyethane (5 mL, 0.157 mmol). 4-methylbenzenesulfonicacid (0.540 mg, 0.00314 mmol) was then added, and the reaction heated to80° C. for 1 hour. The reaction mixture was concentrated in vacuo, andthe residue was purified by flash column chromatography (20-50% ethylacetate/hexanes), to afford 75 mg (72% yield) of the desired product asa yellow solid on standing.

Step D: Preparation of tert-butyl3-(5-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl-carbamate:t-Butyl3-(2-(3-(tert-butyldimethylsilyloxy)phenyl)-5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate(75 mg, 0.113 mmol) was weighed into a 25 mL flask and dissolved in 10.0mL of THF, then cooled to 0° C. TBAF (0.39 mL, 0.39 mmol) was addeddropwise and the reaction mixture was allowed to warm to roomtemperature overnight. The reaction mixture was concentrated to dryness,then re-dissolved in DCM, washed with saturated NaHCO₃ solution, driedover Na₂SO₄, and concentrated in vacuo. The residue was purified byremoval of tributylamine via successive washes with 1N HCl. The organiclayer was concentrated in vacuo, and the yellow oil subject topurification by flash column chromatography (25-60% ethylacetate/hexanes) to afford the desired product (51 mg, 82% yield) as ayellow foam.

Step E: Preparation of3-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)phenol:Tert-butyl3-(5-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate(51 mg, 0.093 mmol) was weighed into a 25 mL flask, and dissolved in 7mL of Et₂O/DCM (1:1). HCl-Et₂O (1.8 mL, 1.863 mmol) was added, and thereaction mixture was stirred at room temperature for 2 hours. Anadditional 20 equivalents of HCl-Et₂O was added and the reaction mixturewas stirred an additional 2 hours. The crude reaction mixture wasconcentrated in vacuo to afford a yellow solid. The solid was thenpurified by flash column chromatography (10-40% MeOH/DCM), affording thedesired product (31 mg, 74% yield) as a yellow foam. MS ESI (+) m/z 448(M+1) detected; ¹H NMR (400 MHz, DMSO-D₆) δ 7.90 (m, 1H), 7.51 (m, 2H),7.19 (m, 1H), 6.84 (m, 2H), 6.74 (m, 1H), 3.21 (m, 1H), 2.98 (m, 1H),2.89 (m, 2H), 2.56 (m, 3H), 2.61 (m, 1H), 2.10 (m, 1H), 1.60 (m, 1H).

Example 20

3-(3-(5-bromo-1,3,4-thiadiazol-2-yl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine

Step A: Preparation of2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothiohydrazide:2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole(577 mg, 1.61 mmol) was dissolved in 8 mL THF, followed by addition ofthio-carbonyldiimidazole (458 mg, 2.57 mmol), and heated to reflux for 1hour. The reaction mixture was cooled to 23° C., and hydrazine (257 mg,8.03 mmol) was added. The reaction mixture was stirred for 12 hours. Thecrude reaction mixture was then concentrated and purified by flashcolumn chromatography, eluting with 4:1 (hexanes/ethyl acetate), toafford the desired product (135 mg, 20%).

Step B:2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-1,3,4-thiadiazole:2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothiohydrazide(220 mg, 0.51 mmol) was dissolved in trimethyl-orthoformate (1.62 g,15.2 mmol) with a few crystals of pTsOH (10 mg, 0.05 mmol), and heatedto 80° C. for 20 minutes. The reaction mixture was then concentrated andpurified by flash column chromatography, eluting with 4:1 (hexanes/ethylacetate), to afford the desired product as a light yellow oil (202 mg,90%).

Step C: Preparation of2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5-bromo-1,3,4-thiadiazole:2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-1,3,4-thiadiazole(0.020 g, 0.0451 mmol) was dissolved in 0.25 mL ACN, followed byaddition of N-Bromosuccinimide (0.00883 g, 0.0496 mmol), and thereaction mixture was heated at 60° C. for 14 hours. The reaction mixturewas concentrated, and the residue was partitioned between ethyl acetateand saturated sodium bicarbonate solution. The organic layer was washedwith brine, dried over Na₂SO₄, filtered, and concentrated. The crudematerial was then purified by flash column chromatography, eluting with5.3:1 (hexanes/ethyl acetate), to afford the desired product as a thickgolden oil (22 mg, 93%).

Step D: Preparation of3-(3-(5-bromo-1,3,4-thiadiazol-2-yl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine:2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5-bromo-1,3,4-thiadiazole(0.006 g, 0.011 mol) was dissolved in 0.25 mL THF, followed by additionof water (0.015 g, 15 μL) and triphenylphosphine (0.015 g, 0.057 mmol),and the reaction mixture was stirred at 23° C. overnight. The crudemixture was purified by directly loading onto a preparative TLC plateand eluting first with 12:1 (DCM:MeOH), followed by a second elutionwith 10:1 (DCM:MeOH) (both with NH₄OH present), to afford the desiredproduct (0.003 g, 53%). MS ESI (+) m/z 495/497 (M+1) detected; ¹H NMR(400 MHz, CDCl₃) δ 7.52 (m, 3H), 7.35 (t, 2H, J=7.6 Hz), 7.30 (d, 1H,J=7.2 Hz), 7.12 (m, 2H), 3.46 (m, 1H), 2.65 (m, 6H), 2.05 (m, 1H), 1.61(m, 1H).

Example 21

3-(5-(2,5-difluorophenyl)-3-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine

Step A: Preparation ofN-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole-3-carbonothioyl)benzamide:To a solution of2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole(1.00 g, 2.79 mmol) in 20 mL of anhydrous THF was added benzoylisothiocyanate (0.45 mL, 3.34 mmol). The reaction was allowed to stirovernight at reflux, then cooled and concentrated in vacuo. The residuewas purified by flash column chromatography (5-35% ethylacetate/hexanes) to afford the desired product as a yellow gum, 1.45 g,54%.

Step B: Preparation of2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothioamide:To a solution ofN-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole-3-carbonothioyl)benzamide(0.737 g, 1.41 mmol) in 20 mL of anhydrous THF was added hydrazine(0.088 mL, 2.82 mmol). The reaction was stirred at room temperature for3 hours, then concentrated in vacuo. The residue was purified by flashcolumn chromatography (10-20% ethyl acetate/hexanes) to afford thedesired product as a pale yellow foam, 0.504 g, 85%.

Step C: Preparation of tert-butyl2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate: To a solution of2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothioamide(0.300 g, 0.717 mmol) in 10 mL of ethanol was added tert-butyl3-bromo-4-oxopiperidine-1-carboxylate (0.239 g, 0.860 mmol) followed byDIEA (0.25 mL, 1.43 mmol). The mixture was allowed to stir overnight atreflux, then treated with tert-butyl3-bromo-4-oxopiperidine-1-carboxylate (100 mg) and stirred at reflux fora further 3 hours. The cooled mixture was partitioned between asaturated NaHCO₃ solution (30 mL) and EtOAc (30 mL), and the aqueouslayer was extracted with EtOAc (2×20 mL). The combined organic phaseswere washed with brine (20 mL), dried over Na₂SO₄, and concentrated invacuo. The residue was purified by flash column chromatography (5-10%ethyl acetate/hexanes) to afford the desired product as a bright yellowfoam, 0.313 g, 73%.

Step D: Preparation of2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine:To a solution of tert-butyl2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(0.313 g, 0.524 mmol) in 10.0 mL of DCM at 0° C. was added TFA (1 mL).The mixture was stirred for 1 hour at 0° C. then at room temperature for1 hour. The reaction mixture was then concentrated to dryness andpartitioned between EtOAc (30 mL) and a saturated NaHCO₃ solution (30mL). The aqueous layer was extracted with EtOAc (2×20 mL), and thecombined organic phases were washed with brine (20 mL), dried overNa₂SO₄ and concentrated in vacuo to afford the desired product as ayellow gum, 0.251 g, 96%.

Step E: Preparation of2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine:To a solution of2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine(0.050 g, 0.100 mmol) in 1 mL DCE was added formaldehyde (0.033 g, 37 wt% in water, 0.401 mmol), followed by sodium triacetoxy borohydride(0.023 g, 0.110 mmol). The resulting suspension was stirred vigorouslyat room temperature overnight, then treated with saturated Na₂CO₃solution (10 mL) and stirred for 10 minutes. The mixture was extractedwith EtOAc (3×10 mL) and the combined organic phases were washed withbrine (10 mL), dried over Na₂SO₄ and concentrated in vacuo. The residuewas purified by flash column chromatography (0-3% MeOH/DCM) to affordthe desired product as a yellow foam, 0.046 g, 89%.

Step F: Preparation of3-(5-(2,5-difluorophenyl)-3-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine:To a solution of2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine(0.046 g, 0.090 mmol) in 2 mL of methanol was added 1N HCl/MeOH (0.27mL, 0.27 mmol) followed by 10% Pd/C (10 mg). The mixture washydrogenated under a balloon atmosphere for 1 hour then filtered throughGF paper, and the filtrate concentrated in vacuo. The residue wastriturated with diethyl ether, filtered, washed with ether and dried invacuo to afford the desired product as a bright yellow solid, 0.027 g,50%. MS ESI (+) m/z 486 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.59(m, 1H), 7.45 (d, 2H, J=7.6 Hz), 7.32 (m, 2H), 7.26 (m, 1H), 7.06 (m,2H), 3.50 (m, 2H), 3.43 (m, 1H), 2.77 (t, 2H, J=6.9 Hz), 2.68 (m, 2H),2.56 (m, 2H), 2.46 (s, 3H), 2.41 (m, 1H), 1.99 (m, 1H), 1.55 (m, 1H)ppm.

Example 22

3-(5-(2,5-difluorophenyl)-2-phenyl-3-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine

To a solution of2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine(prepared according to Example 21, Steps A-D; 0.050 g, 0.100 mmol) in 2mL of methanol was added 1N HCl/MeOH (0.30 mL, 0.30 mmol) followed by10% Pd/C (10 mg). The mixture was hydrogenated under a balloonatmosphere for 1 hour then filtered through GF paper, and the filtrateconcentrated in vacuo. The residue was triturated with diethyl ether,filtered, washed with ether and dried in vacuo to afford the desiredproduct as a bright yellow solid, 0.018 g, 31%. MS ESI (+) m/z 472 (M+1)detected; ¹H NMR (400 MHz, CDCl₃) δ 7.59 (m, 1H), 7.46 (m, 2H), 7.33 (m,3H), 7.05 (m, 2H), 3.88 (m, 2H), 3.46 (m, 1H), 3.06 (m, 2H), 2.79 (m,2H), 2.44 (m, 3H), 2.01 (m, 1H), 1.57 (m, 1H) ppm.

Example 23

3-(5-(2,5-difluorophenyl)-3-(4,5-dimethylthiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine

2-(3-Azidopropyl)-5-(2,5-difluorophenyl)-3-(4,5-dimethylthiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazolewas prepared as in Example 21, Step C, utilizing 3-chlorobutan-2-one inplace of tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate. Reduction ofthe azide as in Example 21, Step F afforded the desired product as ayellow powder, 25%. MS ESI (+) m/z 445 (M+1) detected; ¹H NMR (400 MHz,CDCl₃) δ 7.59 (m, 1H), 7.47 (d, 2H, J=7.6 Hz), 7.33 (m, 3H), 7.04 (m,2H), 3.45 (m, 1H), 2.78 (m, 2H), 2.43 (m, 1H), 2.19 (s, 3H), 1.99 (m,1H), 1.97 (s, 3H), 1.58 (m, 1H) ppm.

Example 24

2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-N,N-dimethylthiazole-4-carboxamide

Step A: Preparation of ethyl2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)thiazole-4-carboxylate:Prepared from2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothioamideas in Example 21, Step C, utilizing ethyl 3-bromo-2-oxopropanoate inplace of tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate, 57%.

Step B: Preparation of2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-N,N-dimethylthiazole-4-carboxamide:To a solution of dimethylamine (0.102 mL, 2.0 M, 0.2 mmol) in 1 mL ofanhydrous THF was added trimethylaluminum (0.102 mL, 2.0 M, 0.2 mmol).The solution was stirred at room temperature for 15 minutes, thentreated with a solution of ethyl2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)thiazole-4-carboxylate(0.035 g, 0.07 mmol) in 0.5 mL of anhydrous THF. After stirring at roomtemperature for 16 hours the mixture was treated with 0.5 N aqueousRochelle's salt solution (10 mL), then partitioned between saturatedNH₄Cl (10 mL) and EtOAc (10 mL). The aqueous layer was extracted withEtOAc (2×10 mL) and the combined organic phases were washed with brine(10 mL), dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography (20-35% ethyl acetate/hexanes)to afford the desired product as a yellow gum, 0.026 g, 74%.

Step C: Preparation of2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-N,N-dimethylthiazole-4-carboxamide:2-(2-(3-Azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-N,N-dimethylthiazole-4-carboxamide(0.026 g, 0.051 mmol) was reduced as in Example 21, Step F, to affordthe desired product as a yellow powder, 0.024 g, 60%. MS ESI (+) m/z 488(M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.63 (m, 1H), 7.50 (d, 2H, J=8Hz), 7.31 (m, 3H), 7.24 (m, 1H), 7.10 (m, 2H), 3.29 (m, 1H), 2.92 (s,3H), 2.78 (m, 2H), 2.51 (s, 3H), 2.41 (m, 1H), 1.99 (m, 1H), 1.51 (m,1H) ppm.

Example 25

2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-N-methylthiazole-4-carboxamide

Prepared in an analogous manner to Example 24, utilizing methylamine inplace of dimethylamine in Step B, to afford the desired product as ayellow solid, 80%. MS ESI (+) m/z 474 (M+1) detected; ¹H NMR (400 MHz,CD₃OD) δ 7.62 (m, 1H), 7.53 (m, 3H), 7.38 (m, 2H), 7.30 (m, 3H), 3.63(m, 1H), 3.10 (m, 2H), 2.79 (s, 3H), 2.72 (m, 1H), 2.29 (m, 1H), 1.82(m, 1H) ppm.

Example 26

3-(5-(2,5-difluorophenyl)-3-(3-methyl-1H-1,2,4-triazol-5-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine

Step A: Preparation of methyl2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbimidothioate:To a solution of2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothioamide(0.120 g, 0.29 mmol) in 2 mL of a 4:1 mixture of DCM:MeOH was addedmethyl iodide (0.022 mL, 0.34 mmol). After stirring for 16 hours at roomtemperature, methyl iodide (0.050 mL) was added and the mixture stirredfor a further 4 hours then concentrated in vacuo. The residue waspartitioned between saturated NaHCO₃ (10 mL) and EtOAc (10 mL) and theaqueous layer was extracted with EtOAc (2×10 mL). The combined organicphases were washed with brine (10 mL), dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash columnchromatography (10-20% ethyl acetate/hexanes) to afford the desiredproduct, 0.124 g, 59%.

Step B: Preparation of2-(3-azidopropyl)-5-(2,5-difluorophenyl)-3-(3-methyl-1H-1,2,4-triazol-5-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole:To a solution of methyl2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbimidothioate(0.034 g, 0.079 mmol) in 1 mL pyridine was added acetohydrazide (0.017g, 0.240 mmol). The mixture was warmed to 80° C. and stirred for 16hours, then treated with acetohydrazide (0.050 g) and stirred at refluxfor 40 hours. The cooled mixture was treated with water (10 mL) andextracted with EtOAc (3×10 mL). The combined organic phases were washedwith water (10 mL) and brine (10 mL), then dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash columnchromatography (10-20% ethyl acetate/hexanes) to afford the desiredproduct as a pale yellow solid, 0.010 g, 29%.

Step C: Preparation of3-(5-(2,5-difluorophenyl)-3-(3-methyl-1H-1,2,4-triazol-5-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine:2-(3-Azidopropyl)-5-(2,5-difluorophenyl)-3-(3-methyl-1H-1,2,4-triazol-5-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole(0.010 g, 0.023 mmol) was reduced as in Example 21, Step F, to affordthe desired product as a pale green solid, 0.007 g, 63%. MS ESI (+) m/z414 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.45 (m, 3H), 7.33 (m,2H), 7.27 (m, 1H), 7.20 (m, 2H), 3.30 (m, 1H), 2.97 (m, 2H), 2.62 (m,1H), 2.24 (s, 3H), 2.18 (m, 1H), 1.74 (m, 1H) ppm.

Example 27

2-(5-(2,5-difluorophenyl)-3-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethanol

Step A: Preparation of2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole:To a solution of 3-(tert-butyldiphenylsilyloxy)-1-phenylpropan-1-one(1.98 g, 5.10 mmol) in 20 mL of a 3:1 mixture of EtOH:DCM was added2,5-difluorobenzothiohydrazide (0.800 g, 4.25 mmol). The mixture wasallowed to stir capped, at room temperature for 60 hours, then uncappedfor 48 hours and then concentrated in vacuo. The residue was purified byflash column chromatography (Hexanes) to afford the desired product asan orange oil, 2.19 g, 92% which was contaminated with3-(tert-butyldiphenylsilyloxy)-1-phenylpropan-1-one. The compound wascarried forward to the next step without further purification.

Step B: Preparation ofN-(2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole-3-carbonothioyl)benzamide:To a solution of2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole(1.00 g, 1.79 mmol) in 20 mL of anhydrous THF was added benzoylisothiocyanate (0.29 mL, 2.15 mmol). The reaction was allowed to stirovernight at reflux then cooled and concentrated in vacuo. The residuewas purified by flash column chromatography (5-10% ethylacetate/hexanes) to afford the desired product as a yellow foam, 0.677g, 52%.

Step C: Preparation of2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothioamide:To a solution ofN-(2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole-3-carbonothioyl)benzamide(0.677 g, 0.938 mmol) in 20 mL of anhydrous THF was added hydrazine(0.060 mL, 1.87 mmol). The reaction was stirred at room temperature for3 hours then concentrated in vacuo. The residue was purified by flashcolumn chromatography (5-10% ethyl acetate/hexanes) to afford thedesired product as a pale yellow foam, 0.502 g, 87%.

Step D: Preparation of tert-butyl2-(2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate:To a solution of2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothioamide(0.500 g, 0.809 mmol) in 20 mL of ethanol was added tert-butyl3-bromo-4-oxopiperidine-1-carboxylate (0.338 g, 1.21 mmol) followed byDIEA (0.423 mL, 2.43 mmol). The mixture was allowed to stir overnight atreflux then treated with tert-butyl3-bromo-4-oxopiperidine-1-carboxylate (200 mg) and stirred at reflux fora further 3 hours. The cooled mixture was partitioned between saturatedNaHCO₃ solution (50 mL) and EtOAc (50 mL) and the aqueous layer wasextracted with EtOAc (2×50 mL). The combined organic phases were washedwith brine (50 mL) dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography (5-10% ethylacetate/hexanes) to afford the desired product as a viscous yellow oil,0.412 g, 64%.

Step E: Preparation of2-(2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine:To a solution of tert-butyl2-(2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(0.180 g, 0.226 mmol) in 4 mL of DCM at 0° C. was added TFA (1 mL). Themixture was stirred for 1 hour at 0° C. for 3 hours then concentrated invacuo. The residue was partitioned between EtOAc (20 mL) and saturatedNaHCO₃ solution (20 mL) and the aqueous layer was extracted with EtOAc(2×10 mL). The combined organic phases were washed with brine (10 mL),dried over Na₂SO₄ and concentrated in vacuo to afford the desiredproduct as a yellow gum, 0.157 g, 100%.

Step F: Preparation of2-(2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine:To a solution of2-(2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-4,5,6,7-tetrahydrothiazol[5,4-c]pyridine(0.157 g, 0.225 mmol) in 5 mL DCE was added formaldehyde (0.067 mL, 37wt % in water, 0.901 mmol) followed by sodium triacetoxyborohydride(0.052 g, 0.248 mmol). The resulting suspension was stirred vigorouslyat room temperature overnight, then treated with saturated Na₂CO₃solution (30 mL) and stirred for 10 minutes. The mixture was extractedwith EtOAc (3×30 mL) and the combined organic phases were washed withbrine (20 mL), dried over Na₂SO₄ and concentrated in vacuo. The residuewas purified by flash column chromatography (0-1% MeOH/DCM) to affordthe desired product as a bright yellow foam, 0.119 g, 74%.

Step G: Preparation of2-(5-(2,5-difluorophenyl)-3-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethanol:To a solution of2-(2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine(0.070 g, 0.098 mmol) in 2 mL of anhydrous acetonitrile was added HF-TEA(0.160 mL, 0.99 mmol). The solution was stirred at room temperature for16 hours then slowly quenched with saturated NaHCO₃ (20 mL). The mixturewas extracted with EtOAc (3×10 mL) and the combined organic phases werewashed with brine (10 mL), dried over Na₂SO₄ and concentrated in vacuo.The residue was purified by flash column chromatography (0-1% MeOH/DCM)and the residue was dissolved in 2 mL of methanol and treated with 1NHCl/MeOH (2 mL). After stirring for 10 minutes, the solution wasconcentrated in vacuo. The residue was triturated with diethyl ether,filtered, washed with ether and dried in vacuo to afford the desiredproduct as a yellow powder, 0.023 g, 42%. MS ESI (+) m/z 473 (M+1)detected; ¹H NMR (400 MHz, CDCl₃) δ 7.59 (m, 1H), 7.44 (d, 2H, J=7.5Hz), 7.32 (m, 2H), 7.26 (m, 1H), 7.07 (m, 2H), 4.10 (m, 1H), 3.96 (m,1H), 3.65 (m, 1H), 3.54 (q, 2H, J=30.2, 14.3 Hz), 2.83 (m, 1H), 2.72 (m,2H), 2.57 (m, 2H), 2.48 (s, 3H) ppm.

Example 28

2-(5-(2,5-difluorophenyl)-2-phenyl-3-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethanol

To a solution of tert-butyl2-(2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6,7-dihydrothiazolhydro[5,4-c]pyridine-5(4H)-carboxylate(prepared according to Example 26, Steps A-D; 0.090 g, 0.113 mmol) in 1mL of 1,4-dioxane was added 4M HCl/dioxane (1 mL). The mixture wasstirred at room temperature for 16 hours then treated with 4MHCl/dioxane (2 mL) and stirred for a further 3 hours. Water (1 mL) wasadded and the mixture was stirred for 16 hours then concentrated anddried in vacuo. The residue was triturated with diethyl ether, filtered,washed with ether and dried in vacuo to afford the desired product as anorange/yellow solid, 0.023 g, 38%. MS ESI (+) m/z 459 (M+1) detected; ¹HNMR (400 MHz, CDCl₃) δ 7.59 (m, 1H), 7.46 (m, 2H), 7.33 (m, 3H), 7.07(m, 2H), 4.12 (m, 1H), 3.95 (m, 1H), 3.87 (m, 2H), 3.65 (m, 2H), 3.05(m, 2H), 2.84 (m, 1H), 2.43 (m, 2H) ppm.

The following compounds can also be prepared using the above describedprocedures, utilizing the appropriately substituted reagents.

R⁴ Name 29

3-(5-(2,5-difluorophenyl)-2-phenyl-3-(pyridin-3-yl)-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 30

3-(5-(2,5-difluorophenyl)-2-phenyl-3-(pyridin-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 31

3-(5-(2,5-difluorophenyl)-2-phenyl-3-(pyridin-4-yl)-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 32

3-(5-(2,5-difluorophenyl)-3-(3-methylpyridin-4-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 33

3-(5-(2,5-difluorophenyl)-3-(3-(fluoromethyl)pyridin-4-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 34

3-(3-(3-(difluoromethyl)pyridin-4-yl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 35

3-(5-(2,5-difluorophenyl)-2-phenyl-3-(3-(trifluoromethyl)pyridin-4-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 36

3-(5-(2,5-difluorophenyl)-3-(3-nitropyridin-4-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 37

(4-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)pyridin-3- yl)methanol 38

4-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-N,N- dimethylnicotinamide 39

3-(4-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)pyridin-3-yl)-1-methoxy-1- methylurea 40

3-(5-(2,5-difluorophenyl)-3-(3- ((dimethylamino)methyl)pyridin-4-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 41

3-(5-(2,5-difluorophenyl)-3-(3,5-dimethylpyridin-4-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 42

3-(5-(2,5-difluorophenyl)-3-(3-ethylpyridin-4-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 43

3-(3-(3-chloropyridin-4-yl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 44

4-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)- yl)nicotinonitrile 45

3-(5-(2,5-difluorophenyl)-3-(2-fluoropyridin-4-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 46

3-(5-(2,5-difluorophenyl)-2-phenyl-3-(pyrimidin-2-yl)-2,3-dihydro-1,3,4-thiadiazol- 2-yl)propan-1-amine 47

3-(5-(2,5-difluorophenyl)-3-(4-methylpyrimidin-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 48

3-(5-(2,5-difluorophenyl)-3-(5-fluoro-4-methylpyrimidin-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 49

(2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)pyrimidin- 4-yl)methanol 50

2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-N,N-dimethylpyrimidine-4-carboxamide 51

3-(5-(2,5-difluorophenyl)-3-(4-((dimethylamino)methyl)pyrimidin-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 52

3-(3-(5-chloropyrimidin-2-yl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 53

2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)- yl)pyrimidine-4-carbonitrile 54

3-(5-(2,5-difluorophenyl)-3-(4-nitropyrimidin-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 55

3-(5-(2,5-difluorophenyl)-3-(2-methylthiazol-5-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 56

2′-(3-aminopropyl)-5′-(2,5-difluorophenyl)-4-methyl-2′-phenyl-2′H-2,3′-bi(1,3′,4′- thiadiazol)-5(4H)-one 57

2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-1,4- dimethyl-1H-imidazol-5(4H)-one58

2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-1,5,5-trimethyl-1H-imidazol-4(5H)-one 59

3-(5-(2,5-difluorophenyl)-3-(4-methoxythiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 60

(5R)-4-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5-methyloxazol-2(5H)-one 61

(5R)-4-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5-methylthiazole-2(5H)-thione 62

(5R)-4-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5-methylthiazol-2(5H)-one 63

4-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-phenyl-3(2H)-yl)-1,5,5- trimethyl-1H-imidazol-2(5H)-one64

4-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5,5- dimethyloxazol-2(5H)-one 65

4-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5,5- dimethylthiazol-2(5H)-one 66

2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5,5- dimethylthiazol-4(5H)-one 67

2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5,5- dimethyloxazol-4(5H)-one 68

5-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6,6-dimethyl-2H-1,4-oxazin-3(6H)-one 69

5-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6,6-dimethyl-2H-1,4-thiazin-3(6H)-one 70

3-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-4,4-dimethyl-6H-1,2,5-dithiazin-1,1-dioxide 71

3-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-4,4-dimethyl-6H-1,2,5-oxathiazin-1,1-dioxide 72

3-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5-methyl-6H-1,2,4-dithiazin-1,1-dioxide 73

3-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5-methyl-1,2,4-dithiazin-1,1-dioxide 74

3-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5-methyl-1,2,4-oxathiazin-1,1-dioxide 75

2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6-methyl- 4H-1,3-oxazin-4-one 76

2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6,6-dimethyl-5,6-dihydro-4H-1,3-thiazin-4-one 77

2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6,6-dimethyl-5,6-dihydro-4H-1,3-oxazin-4-one 78

2-(2,-3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-4-one 79

2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5,5-dimethyl-5,6-dihydro-4H-1,3-thiazin-4-one 80

3-(5-(2,5-difluorophenyl)-3-(1,4-dimethyl-1H-imidazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 81

3-(5-(2,5-difluorophenyl)-3-(1,5-dimethyl-1H-imidazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 82

3-(5-(2,5-difluorophenyl)-3-(1-methyl-1H-imidazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 83

3-(5-(2,5-difluorophenyl)-3-(1-methyl-1H-pyrazol-3-yl)-2-phenyl-2,3-dihydro-1,3,4- thiadiazol-2-yl)propan-1-amine84

3-(5-(2,5-difluorophenyl)-3-(1,3-dimethyl-1H-pyrazol-5-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 85

3-(5-(2,5-difluorophenyl)-3-(1,4-dimethyl-1H-pyrazol-5-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 86

3-(5-(2,5-difluorophenyl)-3-(4-methyl-1H-pyrazol-5-yl)-2-phenyl-2,3-dihydro-1,3,4- thiadiazol-2-yl)propan-1-amine87

3-(5-(2,5-difluorophenyl)-3-(4-methylthiazol-5-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 88

3-(5-(2,5-difluorophenyl)-3-(5-methylthiazol-4-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 89

3-(5-(2,5-difluorophenyl)-3-(2-methylthiazol-4-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 90

3-(5-(2,5-difluorophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 91

3-(5-(2,5-difluorophenyl)-3-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 92

5-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methyl- 1,2,4-thiadiazol-3(2H)-one93

3-(5-(2,5-difluorophenyl)-3-(1-methyl-1H-imidazol-4-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 94

3-(5-(2,5-difluorophenyl)-3-(1,5-dimethyl-1H-imidazol-4-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 95

3-(5-(2,5-difluorophenyl)-3-(1,2-dimethyl-1H-imidazol-4-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 96

3-(5-(2,5-difluorophenyl)-2-phenyl-3-(1,2,5-trimethyl-1H-imidazol-4-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 97

3-(5-(2,5-difluorophenyl)-3-(1,2-dimethyl-1H-imidazol-5-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 98

3-(5-(2,5-difluorophenyl)-3-(1,4-dimethyl-1H-imidazol-5-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 99

3-(5-(2,5-difluorophenyl)-2-phenyl-3-(1,2,4-trimethyl-1H-imidazol-5-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 100 

3-(5-(2,5-difluorophenyl)-3-(5-methoxy-4,4-dimethyl-4H-pyrazol-3-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 101 

3-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-4,4- dimethyl-1H-pyrazol-5(4H)-one102 

3-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-1,4,4-trimethyl-1H-pyrazol-5(4H)-one 103 

3-(5-(2,5-difluorophenyl)-3-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 104 

3-(5-(2,5-difluorophenyl)-2-phenyl-3-(1,2,4-thiadiazol-5-yl)-2,3-dihydro-1,3,4-thiadiazol- 2-yl)propan-1-amine 105 

3-(5-(2,5-difluorophenyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 106 

3-(5-(2,5-difluorophenyl)-3-(1,2,4-oxadiazol-5-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 107 

3-(5-(2,5-difluorophenyl)-3-(3-methyl-1,2,4-oxadiazol-5-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 108 

3-(5-(2,5-difluorophenyl)-2-phenyl-3- (6,7,8,8a-tetrahydro-5H-[1,3,4]thiadiazolo[3,2-a]pyridin-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 109 

3-(5-(2,5-difluorophenyl)-3-(8a-methyl-6,7,8,8a-tetrahydro-5H-[1,3,4]thiadiazolo[3,2-a]pyridin-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 110 

2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-8a- methyl-6,7,8,8a-tetrahydro-5H-[1,3,4]thiadiazolo[3,2-a]pyridin-5-one 111 

2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-8a- methyl-6,7,8,8a-tetrahydro-5H-[1,3,4]oxadiazolo[3,2-a]pyridin-5-one 112 

2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5,7,8,8a-tetrahydro-[1,3,4]thiadiazolo[3,2- c][1,3]thiazin-6,6-dioxide 113 

2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-7-methyl-5,7,8,8a-tetrahydro-[1,3,4]thiadiazolo[2,3-d][1,2,5]thiadiazin-6,6-dioxide 114 

3-(5-(2,5-difluorophenyl)-3-(7-methyl-6,7,8,8a-tetrahydro-5H-[1,3,4]thiadiazolo[3,2-a]pyrazin-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 115 

3-(5-(2,5-difluorophenyl)-3-(4-fluoro-5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 116 

3-(5-(2,5-difluorophenyl)-3-(7-fluoro-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2-phenyl-2,3-dehydro-1,3,4-thiadiazol-2-yl)propan-1-amine 117 

2-(2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-4-fluoro-6,7-dihydrothiazolo[4,5- c]pyridin-5(4H)-yl)ethanol118 

2-(2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-4-fluoro-6,7-dihydrothiazolo[4,5- c]pyridin-5(4H)-yl)ethyldihydrogen 119 

3-(5-(2,5-difluorophenyl)-3-(5-(2-(dimethylamino)ethyl)-4-fluoro-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 120 

2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-4-fluoro- N-methoxy-N-methyl-6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)- carboxamide 121 

2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-N-cyano-4-fluoro-6,7-dihydrothiazolo[4,5-c]pyridine- 5(4H)-carboximidamide 122 

3-(5-(2,5-difluorophenyl)-3-(5-(4- morpholinobutyl)-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 123 

3-(5-(2,5-difluorophenyl)-3-(5-(3- morpholinopropyl)-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 124 

3-(5-(2,5-difluorophenyl)-3-(4- (fluoromethyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 125 

3-(3-(4-(difluoromethyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 126 

3-(5-(2,5-difluorophenyl)-3-(5-methyl-4- (trifluoromethyl)-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 127 

3-(5-(2,5-difluorophenyl)-3-(5,7-dimethyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 128 

3-(5-(2,5-difluorophenyl)-3-(4-methyl-4,5,6,7-tetrahydrothiazolo[5,4-b]pyridin-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 129 

2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-N,N,4-trimethyl-4,5,6,7-tetrahydrothiazolo[4,5- b]pyridine-6-carboxamide 130 

3-(5-(2,5-difluorophenyl)-3-(5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 131 

3-(5-(2,5-difluorophenyl)-3-(5-(methylsulfonyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 132 

3-(5-(2,5-difluorophenyl)-3-(4,6-dihydrothieno-5,5-dioxo-[3,4-d]thiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 133 

3-(5-(2,5-difluorophenyl)-3-(4-methyl-5,6-dihydro-4H-pyrrolo[2,3-d]thiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 134 

3-(5-(2,5-difluorophenyl)-3-(1-methyl-1,3-dihydroisothiazolo-2,2-dioxo-[3,4-d]thiazol-5-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 135 

3-(5-(2,5-difluorophenyl)-3-(4-methyl-5,6-dihydro-4H-pyrrolo[3,2-d]thiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 136 

3-(5-(2,5-difluorophenyl)-3-(1-methyl-1,3-dihydroisothiazolo-2,2-dioxo-[4,3-d]thiazol-5-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 137 

3-(5-(2,5-difluorophenyl)-3-(4-methyl-4H-pyrrolo[3,2-d]thiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 138 

3-(5-(2,5-difluorophenyl)-3-(1-methyl-1H-pyrazolo[4,3-d]thiazol-5-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 139 

3-(5-(2,5-difluorophenyl)-3-(2-methyl-2H-thieno[2,3-c]pyrazol-5-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 140 

3-(5-(2,5-difluorophenyl)-3-(4-fluoro-5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 141 

3-(3-(benzo[d]thiazol-2-yl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 142 

3-(5-(2,5-difluorophenyl)-3-(4-methylbenzo[d]thiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 143 

3-(5-(2,5-difluorophenyl)-3-(7-methylbenzo[d]thiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 144 

3-(5-(2,5-difluorophenyl)-3-(6-methylbenzo[d]thiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 145 

3-(5-(2,5-difluorophenyl)-3-(5-methylbenzo[d]thiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 146 

3-(5-(2,5-difluorophenyl)-3-(7- ethylbenzo[d]thiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 147 

3-(5-(2,5-difluorophenyl)-3-(7-fluorobenzo[d]thiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 148 

3-(5-(2,5-difluorophenyl)-3-(4-fluorobenzo[d]thiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 149 

3-(3-(5-chlorobenzo[d]thiazol-2-yl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 150 

3-(3-(6-chlorobenzo[d]thiazol-2-yl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 151 

3-(5-(2,5-difluorophenyl)-3-(6- ethylbenzo[d]thiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 152 

2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)- yl)benzo[d]thiazole-6-carbonitrile 153 

3-(5-(2,5-difluorophenyl)-3-(6- nitrobenzo[d]thiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 154 

3-(2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)benzo[d]thiazol-6-yl)-1,1- dimethylurea 155 

2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-N,N-dimethylbenzo[d]thiazole-6-carboxamide 156 

(2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)- yl)benzo[d]thiazol-6-yl)methanol 157 

3-(5-(2,5-difluorophenyl)-3-(6-((dimethylamino)methyl)benzo[d]thiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 158 

3-((2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-1- methoxy-1-methylurea 159 

3-(5-(2,5-difluorophenyl)-3-(6-(3-methyl-1H-1,2,4-triazol-1-yl)benzo[d]thiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 160 

3-(3-(benzo[d]oxazol-2-yl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 161 

3-(5-(2,5-difluorophenyl)-3-(1-methyl-1H-benzo[d]imidazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 162  

2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-N,N-dimethyl-6,7-dihydrothiazolo[4,5-c]pyridine- 5(4H)-carboxamide 163 

2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-N,N-dimethyl-6,7-dihydrothiazolo[5,4-c]pyridine- 5(4H)-carboxamide 164 

3-(5-(2,5-difluorophenyl)-3-(6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 165 

3-(5-(2,5-difluorophenyl)-3-(imidazo[1,2-b]pyridazin-7-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 166 

3-(5-(2,5-difluorophenyl)-2-phenyl-3-(1H-pyrrolo[3,2-b]pyridin-6-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 167 

3-(5-(2,5-difluorophenyl)-2-phenyl-3-(7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 168 

3-(5-(2,5-difluorophenyl)-2-phenyl-3-(thieno[2,3-d]pyrimidin-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 169 

3-(5-(2,5-difluorophenyl)-3-(6-methylthieno[2,3-d]pyrimidin-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1- amine 170 

3-(5-(2,5-difluorophenyl)-3-(2-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 171 

3-(5-(2,5-difluorophenyl)-3-(2- methylimidazo[1,2-a]pyrimidin-7-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 172 

2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-4H- benzo[e][1,3]oxazin-4-sulphone173 

2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-4H- benzo[e][1,3]thiazin-4-sulphone174 

2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-4H- benzo[e][1,3]thiazin-4-one 175 

2-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6-methyl-6,7-dihydropyrrolo[3,4-e][1,3]thiazin-4(5H)- one

Ar² Name 176 2-methylphenyl 3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-o-tolyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 177 3-methylphenyl3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-m-tolyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 178 4-methylphenyl3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-p-tolyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 179 3,4-dimethylphenyl3-(5-(2,5-difluorophenyl)-2-(3,4-dimethylphenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 180 3,5-dimethylphenyl3-(5-(2,5-difluorophenyl)-2-(3,5-dimethylphenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 181 2-ethylphenyl3-(5-(2,5-difluorophenyl)-2-(2-ethylphenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 182 3-ethylphenyl3-(5-(2,5-difluorophenyl)-2-(3-ethylphenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 183 4-t-butylphenyl3-(2-(4-tert-butylphenyl)-5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 184 2-chlorophenyl3-(2-(2-chlorophenyl)-5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 185 4-chlorophenyl3-(2-(4-chlorophenyl)-5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 186 3-fluorophenyl3-(5-(2,5-difluorophenyl)-2-(3-fluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 187 4-fluorophenyl3-(5-(2,5-difluorophenyl)-2-(4-fluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 188 4-bromophenyl3-(2-(4-bromophenyl)-5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 189 3,4-dichlorophenyl3-(2-(3,4-dichlorophenyl)-5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 190 3-nitrophenyl3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-(3-nitrophenyl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 191 3-hydroxyphenyl3-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4- thiadiazol-2-yl)phenol192

3-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4- thiadiazol-2-yl)phenyldihydrogen phosphate 193 3-aminophenyl3-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4- thiadiazol-2-yl)aniline194 3-carboxyphenyl 3-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4- thiadiazol-2-yl)benzoicacid 195 3-cyanophenyl 3-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)benzonitrile 196 2-pyridyl3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 197 3-pyridyl3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-(pyridin-3-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 198 5-methylthiophen-2-yl3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-(5-methylthiophen-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 199 2-methylthiazol-4-yl3-(5-(2,5-difluorophenyl)-2-methylthiazol-4-yl-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 200 2-(1H-imidazol-2-yl)3-(5-(2,5-difluorophenyl)-2-(1H-imidazol-2-yl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 201 2-(1H-imidazol-4-yl)3-(5-(2,5-difluorophenyl)-2-(1H-imidazol-4-yl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 202 3-amino-1H-pyrazol-5-yl3-(5-(2,5-difluorophenyl)-3-amino-1H-pyrazol-5-yl-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine

Ar¹ Name 203 2-fluoro- 3-(5-(2-fluorophenyl)-3-(5-methyl-1,3,4- phenylthiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 204 3-fluoro-3-(5-(3-fluorophenyl)-3-(5-methyl-1,3,4- phenylthiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 205 2-chloro-3-(5-(2-chlorophenyl)-3-(5-methyl-1,3,4- phenylthiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 206 3-chloro-3-(5-(3-chlorophenyl)-3-(5-methyl-1,3,4- phenylthiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 207 2,5-dichloro-3-(5-(2,5-dichlorophenyl)-3-(5-methyl-1,3,4- phenylthiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 208 2,3-dichloro-3-(5-(2,3-dichlorophenyl)-3-(5-methyl-1,3,4- phenylthiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 209 3,4-dichloro-3-(5-(3,4-dichlorophenyl)-3-(5-methyl-1,3,4- phenylthiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 210 3,5-dichloro-3-(5-(3,5-dichlorophenyl)-3-(5-methyl-1,3,4- phenylthiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 211 2-chloro-5-3-(5-(2-chloro-5-fluorophenyl)-3-(5-methyl-1,3,4- fluorophenylthiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 212 2-fluoro-5-3-(5-(5-chloro-2-fluorophenyl)-3-(5-methyl-1,3,4- chlorophenylthiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 213 2-chloro-5-3-(5-(2-chloro-5-methylphenyl)-3-(5-methyl-1,3,4- methyl-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4- phenylthiadiazol-2-yl)propan-1-amine 214 2-trifluoro- 3-(5-(5-fluoro-2-(trifluoromethyl)phenyl)-3-(5- methyl-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3- 5-fluoro-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine phenyl 215 2-fluoro-5-3-(5-(2-fluoro-5-methoxyphenyl)-3-(5-methyl- methoxy-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4- phenylthiadiazol-2-yl)propan-1-amine 216 thiophen-2-3-(3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-5- yl(thiophen-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 217thiophen-3- 3-(3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-5- yl(thiophen-3-yl)-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 2185-chloro- 3-(5-(5-chlorothiophen-2-yl)-3-(5-methyl-1,3,4- thiophen-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4- 2-ylthiadiazol-2-yl)propan-1-amine 219 2-pyridyl3-(3-(5-methyl-3,4-thiadiazol-2-yl)-2-phenyl-5-(pyridin-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 2203-pyridyl 3-(3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-pheny-5-(pyridin-3-yl)-2,3-dihydro-1,3,4-thiadiazol-2- yl)propan-1-amine 2214-chloro 3-(5-(4-chloropyridin-3-yl)-3-(5-methyl-1,3,4- pyridin-3-ylthiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 222 3-chloro3-(5-(3-chloropyridin-2-yl)-3-(5-methyl-1,3,4- pyridin-2-ylthiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 223 4-fluoro3-(5-(4-fluoropyridin-3-yl)-3-(5-methyl-1,3,4- pyridin-3-ylthiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine 224 3,6-difluoro3-(5-(3,6-difluoropyridin-2-yl)-3-(5-methyl-1,3,4- pyridin-2-ylthiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine

R¹ Name 225

3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)-N-methylpropan-1-amine 226

2-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4- thiadiazol-2-yl)ethanamine227

(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4- thiadiazol-2-yl)methanamine228

3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)-N-isopropylpropan-1-amine 229

2-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)-N-methylethanamine 230

2-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)-N,N-dimethylethanamine 231

2-(5-(2,5-difluorophenyl)-2-phenyl-2-(3-(pyrrolidin-1-yl)propyl)-1,3,4-thiadiazol-3(2H)-yl)-5-methyl-1,3,4-thiadiazole 232

2-(5-(2,5-difluorophenyl)-2-phenyl-2-(3-(piperidin-1-yl)propyl)-1,3,4-thiadiazol-3(2H)-yl)-5-methyl-1,3,4-thiadiazole 233

2-(5-(2,5-difluorophenyl)-2-(3-(4-methylpiperazin-1-yl)propyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5-methyl-1,3,4-thiadiazole 234

4-(3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl)morpholine 235

2-(5-(2,5-difluorophenyl)-2-phenyl-2-(2-(pyrrolidin-2-yl)ethyl)-1,3,4-thiadiazol-3(2H)-yl)-5-methyl-1,3,4-thiadiazole 236

2-(5-(2,5-difluorophenyl)-2-phenyl-2-(piperidin-4-yl)-1,3,4-thiadiazol-3(2H)-yl)-5-methyl-1,3,4- thiadiazole 237

N-(3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl)acetamide 238

N-(3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl)methanesulfonamide 239

N-(3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl)isobutyramide 240

N-(3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4- thiadiazol-2-yl)propyl)-3-(dimethylamino)propanamide 241

2-amino-N-(1-(3-(5-(2,5-difluorophenyl)-3-(5-methyl-134-thiadizol-2-yl)2phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylamino)-1- oxopropan-2-yl)propanamide242

2-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4- thiadiazol-2-yl)ethanol 243

3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4- thiadiazol-2-yl)propan-1-ol244

3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4- thiadiazol-2-yl)propyldihydrogen phosphate

R¹ Name 245

N-(2-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethyl)acetimidamide 246

N-(3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl)acetimidamide 247

N-((5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)methyl)acetimidamide 248

(E)-N-(3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl)-N′- methoxyacetimidamide 249

(E)-N′-cyano-N-(3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3- dihydro-1,3,4-thiadiazol-2-yl)propyl)acetimidamide 250

N-(3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl)-2-fluoroacetimidamide 251

(E)-N-(3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl)-2-nitroethene-1,1- diamine 252

1-(3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl)guanidine 253

(Z)-2-cyano-1-(2-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethyl)guanidine 254

(E)-2-cyano-1-((5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)methyl)guanidine 255

(E)-1-(amino(3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3- dihydro-1,3,4-thiadiazol-2-yl)propylamino)methylene)urea 256

(Z)-1-(amino(2-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3- dihydro-1,3,4-thiadiazol-2-yl)ethylamino)methylene)urea 257

(E)-1-(amino((5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3- dihydro-1,3,4-thiadiazol-2-yl)methylamino)methylene)urea 257

(Z)-N-(amino(3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3- dihydro-1,3,4-thiadiazol-2-yl)propylamino)methylene)acetamide 259

(E)-N-(N′-cyano-N-(3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2- yl)propyl)carbamimidoyl)acetamide 260

(E)-N,N′-((3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3- dihydro-1,3,4-thiadiazol-2-yl)propylamino)methanediylidene)diacetamide 261

(Z)-1-(3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl)-2- methoxyguanidine 262

(Z)-1-(3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl)-2-methylguanidine 263

1-(3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl)-1-methoxyguanidine 264

3-(3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl)-1,1-dimethylguanidine 265

(Z)-1-(3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl)-2,3- dimethylguanidine 266

1-(3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl)tetrahydropyrimidin- 2(1H)-imine 267

N-(3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl)-1,4,5,6- tetrahydropyrimidin-2-amine 268

N-(3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl)pyrrolidine-1- carboximidamide 270

4-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)butanimidamide 271

5-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)pentanimidamide 272

3-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propanimidamide 273

(Z)-4-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)-N'-methoxybutanimidamide 274

(Z)-N′-cyano-4-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)butanimidamide 275

4-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)-2,2-difluorobutanimidamide 276

2-((5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)methoxy)acetimidamide 277

4-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)-N-methylbutanimidamide 278

1-(2-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethoxy)guanidine 280

1-(2-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethoxy)-3-methylguanidine 281

N-(N-(2-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro- 1,3,4-thiadiazol-2-yl)ethoxy)carbamimidoyl)acetamide 282

O-(2-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethyl)-N-(1,4,5,6-tetrahydropyrimidin-2-yl)hydroxylamine 283

N-(2-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethoxy)acetimidamide 284

(E)-N-(2-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethoxy)-N′- methylacetimidamide 285

(E)-N-(1-(2-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3- dihydro-1,3,4-thiadiazol-2-yl)ethoxyamino)ethylidene)acetamide 286

N′-(2-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethyl)acetimidohydrazide 287

(E)-N′-(2-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethyl)-N′- methylacetimidohydrazide 288

(E)-N-(1-(2-(2-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3- dihydro-1,3,4-thiadiazol-2-yl)ethyl)hydrazinyl)ethylidene)acetamide 289

N′-(2-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4- thiadiazol-2-yl)ethyl)-N′-methylacetimidohydrazide 290

2-(2-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethyl)hydrazinecarboximidamide 291

2-(2-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro-1,3,4- thiadiazol-2-yl)ethyl)-N-methylhydrazinecarboximidamide 292

N-((2-(2-(5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenyl-2,3-dihydro- 1,3,4-thiadiazol-2-yl)ethyl)hydrazinyl)(imino)methyl)acetamide 293

2-(5-(2,5-difluorophenyl)-2-phenyl-2-(2-(2-(1,4,5,6-tetrahydropyrimidin-2-yl)hydrazinyl)ethyl)-1,3,4-thiadiazol-3(2H)-yl)-5-methyl-1,3,4-thiadiazole

The biological activities of the compounds of the invention can bedemonstrated by the following assays.

BIOLOGICAL ASSAYS Example A Enzyme Assay

The activity of the compounds of the present invention may be determinedby the following procedure. The assays were conducted at 30° C. in aCostar 3695 (96-well, polystyrene, ½-area, clear) plate in a finalvolume of 50 μL. Hydrolysis of ATP was monitored in a system thatcoupled the product ADP to the oxidation of NADH using pyruvate kinaseand lactate dehydrogenase. Assay mixtures contained the following: 20 mMK⁺Pipes, pH 7.0, 0.01% Triton X-100, 2% DMSO, 25 mM KCl, 2 mM MgCl₂, 1mM DTT, 25 M ATP, 1 mM phospho(enol)pyruvate, 200 μM NADH, 7.9 U/mLpyruvate kinase, 9 U/mL lactate dehydrogenase, 0.25 M bovinemicrotubules, 20 M paclitaxel and 20 nM Eg5. The concentration ofinhibitor was typically varied over the range of 10-200,000 nM. Thereaction was monitored kinetically in an absorbance-based plate readerfor a period of 10 minutes. Velocities were estimated from linear fitsto the progress curves and were expressed as POC (percent of uninhibitedcontrol wells). IC₅₀'s were estimated from the POC data using a standard4-parameter logistical model and compared to a control inhibitor run ineach plate. In this assay, compounds of the invention exhibited an ICso₀of less than 50 jM.

Example B Cell Viability Assay

The ability of the compounds of the present invention to inhibitcellular viability may be determined by the following procedure. Cellsfrom a variety of established tumor cell lines, e.g. HeLa, were platedin Costar 3904 96-well plates, in growth medium, at a density thatallowed for logarithmic growth over the period of the assay, andincubated at 37° C., 5% CO₂ overnight. The following day, compounds wereadded to the cells, at a final DMSO concentration of 0.5%. Theconcentration of inhibitor was typically varied over the range of0.1-50,000 nM. Plates were then incubated as above. After a 72 to 96hour incubation, 20 μL resazurin solution (Cell Titer Blue, PromegaG8081) was added to all wells and the plates incubated for a furtherperiod of time. Viable cells convert resazurin to resorufin, afluorescent end-product. The fluorescent signal was determined in afluorescent plate reader at 560 nm excitation/590 nm emission. The POC(percent of uninhibited control signal) was determined for each well,and the EC₅₀ for inhibition of viability was determined from theinflection point of a standard 4-parameter logistical curve fitted tothe values obtained. In this assay, compounds of the invention exhibitedan EC₅₀ of less than 50 μM.

Example C Mitotic Arrest Assay

Phosphorylation of Histone H3 on Ser10, which peaks in metaphase, is awell-established indicator of mitosis. Phosphorylation in excess ofcontrol cells is indicative of mitotic arrest. The ability of thecompounds of the present invention to induce mitotic arrest wasdetermined by the following procedure. Cells from a variety ofestablished tumor cell lines, e.g. HeLa, were plated in Greiner 655946,96-well, poly-D-lysine coated plates, in growth medium and incubated at37° C., 5% CO₂ overnight. The following day, compounds were added to thecells at a final DMSO concentration of 0.5%. The concentration ofinhibitor was typically varied over the range of 0.1-50,000 nM. Oncecompound was added to the cells, plates were incubated as above. Afterapproximately 16 hours, cells were fixed with cold methanol. Plates wereblocked and labeled with primary antibody to phosphoHistone H3 (SantaCruz Biotechnologies SC-8656-R, 1 μg/mL) and to GapDH (RDI TRK-5G4-6C5).The cells were then labeled with secondary antibodies which wereconjugated to fluorescent dyes emitting in the near infrared range(Molecular Probes Alexa 680, Rockland IR800) and scanned on a LicorOdyssey or Aerius. The integrated intensity of signal for phosphoHistoneH3 was normalized to the signal for GapDH for each well. The POC(percent of completely inhibited control signal) was determined for eachwell, and the EC₅₀ for induction of mitotic arrest was determined fromthe inflection point of a standard 4-parameter logistical curve fittedto the values obtained. In this assay, compounds of the inventionexhibited an EC₅₀ of less than 50 μM.

Example D Tumor Growth Inhibition

The ability of the compounds of this invention to inhibit tumor growthin vivo may be determined by the following procedure, using the HT-29human colon tumor cell line obtained from the American Type Culturecollection (ATCC). HT-29 tumor cells (3-5×10⁶, in a volume of 100 μLPBS) are implanted subcutaneously in the flank of female nude mice.Tumors are allowed to grow to 150-250 mm³ in size. The length and widthof the tumors are measured with calipers, and tumor volume is calculatedusing the formula: volume=(length×width²)/2. The mice are thenrandomized into treatment groups, typically 5 to 8 per group, based ontumor volume. The mice then receive vehicle or compound on days 1, 5, 9by IP injection. Dose is based on weight, measured the day of dosing.Tumor volume and weight are measured twice a week for the duration ofthe study. Mice are kept on study until tumors grow to about 1500 mm³ insize, after which the mice are euthanized by CO₂ inhalation. Tumorvolume data are typically reported as V/V(0), where V=tumor volume onthe day of measurement, and V(0)=tumor volume at day 1.

The foregoing description is considered as illustrative only of theprinciples of the invention. Further, since numerous modifications andchanges will be readily apparent to those skilled in the art, it is notdesired to limit the invention to the exact construction and processshown as described above. Accordingly, all suitable modifications andequivalents may be considered to fall within the scope of the inventionas defined by the claims that follow.

The words “comprise,” “comprising,” “include,” “including,” and“includes” when used in this specification and in the following claimsare intended to specify the presence of stated features, integers,components, or steps, but they do not preclude the presence or additionof one or more other features, integers, components, steps, or groupsthereof.

What is claimed is:
 1. A compound of the Formula I:

and tautomers, and salts thereof, wherein: W is S(O)_(m); m is 0, 1 or2; R¹ is (CH₂)₃NH₂; Ar¹ and Ar² are independently phenyl or a 5 or 6membered heteroaryl ring having 1 to 3 heteroatoms independentlyselected from N, O and S, wherein said heteroaryl is a carbon radicaland said phenyl and heteroaryl are optionally substituted with one ormore groups independently selected from halogen, cyano, nitro, azido,—OR¹⁰, —NR¹⁰R¹¹, —NR¹⁰SO₂R¹³, SO₂NR¹⁰R¹¹, —C(═O)R¹⁰, —C(═O)OR¹⁰,—OC(═O)R¹⁰, —NR¹⁰C(═O)OR¹³, —NR¹⁰C(═O)R¹¹, —C(═O)NR¹⁰R¹¹, —SR¹⁰,—S(O)R¹³, SO₂R¹³, —SO₂NHC(═O)R¹, —NR¹⁰C(═O)NR¹¹R¹², —NR¹⁰C(NCN)NR¹¹R¹²,—NR¹⁰C(H)NR¹¹R¹², —NR¹⁰C(R¹³)NR¹¹R¹², —OP(═O)(OR¹⁰)₂, alkyl, cycloalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl; R⁴ is selected from:

R¹⁰, R¹¹ and R¹² independently are selected from hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl andarylalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, heterocyclyl and arylalkyl are optionally substituted withone or more groups independently selected from oxo (with the provisothat it is not on said aryl or heteroaryl portions), halogen, cyano,nitro, OR¹⁴, —NR¹⁴R¹⁵, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R¹³ is alkyl,alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or arylalkyl,wherein said alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyland arylalkyl are optionally substituted with one to three groupsindependently selected from oxo (with the proviso that it is not on saidaryl or heteroaryl portions), halogen, cyano, nitro, OR¹⁴, NR¹⁴R¹⁵,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, alkyl,cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl,and heterocyclylalkyl, or any two of R¹⁰, R¹¹, R¹² and R¹³ together withthe atoms to which they are attached form a 4 to 10 membered heteroarylor heterocyclic ring, wherein said heteroaryl and heterocyclic rings areoptionally substituted with one to three groups independently selectedfrom oxo (with the proviso that it is not on said heteroaryl ring),halogen, cyano, nitro, OR¹⁴, —NR¹⁴R¹⁵, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R¹⁴ and R¹⁵ areindependently selected from hydrogen, alkyl, alkenyl, lower alkynyl,cycloalkyl, aryl, heteroaryl, heterocyclyl and arylalkyl, or R¹⁴ and R¹⁵together with the atoms to which they are attached form a saturated,partially unsaturated or fully unsaturated 5-6 membered heterocyclyl. 2.The compound of claim 1, wherein Ar¹ is phenyl optionally substitutedwith one or more groups independently selected from halogen, alkyl,—OR¹⁰ or —NR¹⁰R¹¹; or Ar¹ is a heteroaryl selected from thiophenyl orpyridyl, wherein said pyridyl is optionally substituted independentlywith one or more halogen.
 3. The compound of claim 1, wherein Ar¹ isphenyl, 2,4-difluorophenyl, 2-fluorophenyl, 3-fluorophenyl,2-chlorophenyl, 3-chlorophenyl, 2,5-dichlorophenyl, 2,3-dichlorophenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-chloro-5-fluorophenyl,2-fluoro-5-chlorophenyl, 2-chloro-5-methylphenyl,2-trifluoromethyl-5-fluorophenyl, 2-fluoro-5-methoxyphenyl,thiophen-2-yl, thiophen-3-yl, 5-chlorothiophen-2-yl, 2-pyridyl,3-pyridyl, 4-chloropyridin-3-yl, 3-chloropyridin-2-yl,4-fluoropyridin-3-yl, or 3,6-difluoropyridin-2-yl.
 4. The compound ofclaim 1, wherein Ar¹ is phenyl.
 5. The compound of claim 1, wherein Ar²is phenyl optionally substituted with one or more groups independentlyselected from halogen, OR¹⁰, NR¹⁰R¹¹, CN, NO₂, —OP(═O)(OR¹⁰)₂,C(═O)OR¹⁰, or Ar² is a heteroaryl selected from pyridyl, thiophenyloptionally substituted with alkyl, imidazolyl, and pyrazolyl optionallysubstituted with NR¹⁰R¹¹.
 6. The compound of claim 1, wherein Ar² isphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,3,4-dimethylphenyl, 3,5-dimethylphenyl, 2-ethylphenyl, 3-ethylphenyl,4-t-butylphenyl, 2-chlorophenyl, 4-chlorophenyl, 3-fluorophenyl,4-fluorophenyl, 4-bromophenyl, 3,4-dichlorophenyl, 3-nitrophenyl,3-hydroxyphenyl, 3-(OPO₃H₂)-phenyl, 3-aminophenyl, 3-carboxyphenyl,3-cyanophenyl, 2-pyridyl, 3-pyridyl, 5-methylthiophen-2-yl,2-methylthiazol-4-yl, 2-(1H-imidazol-2-yl), 2-(1H-imidazol-4-yl) or3-amino-1H-pyrazol-5-yl.
 7. The compound of claim 1, wherein Ar² is2,4-difluorophenyl.
 8. The compound of claim 2, wherein Ar² is phenyloptionally substituted with one or more groups independently selectedfrom halogen, OR¹⁰, NR¹⁰R¹¹, CN, NO₂, —OP(═O)(OR¹⁰)₂, C(═O)OR¹⁰, or Ar²is a heteroaryl selected from pyridyl, thiophenyl optionally substitutedwith alkyl, imidazolyl, and pyrazolyl optionally substituted withNR¹⁰R¹¹.
 9. The compound of claim 2, wherein Ar² is phenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl,3,5-dimethylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-t-butylphenyl,2-chlorophenyl, 4-chlorophenyl, 3-fluorophenyl, 4-fluorophenyl,4-bromophenyl, 3,4-dichlorophenyl, 3-nitrophenyl, 3-hydroxyphenyl,3-(OPO₃H₂)-phenyl, 3-aminophenyl, 3-carboxyphenyl, 3-cyanophenyl,2-pyridyl, 3-pyridyl, 5-methylthiophen-2-yl, 2-methylthiazol-4-yl,2-(1H-imidazol-2-yl), 2-(1H-imidazol-4-yl) or 3-amino-1H-pyrazol-5-yl.10. The compound of claim 2, wherein Ar² is 2,4-difluorophenyl.
 11. Thecompound of claim 3, wherein Ar² is phenyl optionally substituted withone or more groups independently selected from halogen, OR¹⁰, NR¹⁰R¹¹,CN, NO₂, —OP(═O)(OR¹⁰)₂, C(═O)OR¹⁰, or Ar² is a heteroaryl selected frompyridyl, thiophenyl optionally substituted with alkyl, imidazolyl, andpyrazolyl optionally substituted with NR¹⁰R¹¹.
 12. The compound of claim3, wherein Ar² is phenyl, 2-methylphenyl, 3-methylphenyl,4-methylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2-ethylphenyl,3-ethylphenyl, 4-t-butylphenyl, 2-chlorophenyl, 4-chlorophenyl,3-fluorophenyl, 4-fluorophenyl, 4-bromophenyl, 3,4-dichlorophenyl,3-nitrophenyl, 3-hydroxyphenyl, 3-(OPO₃H₂)-phenyl, 3-aminophenyl,3-carboxyphenyl, 3-cyanophenyl, 2-pyridyl, 3-pyridyl,5-methylthiophen-2-yl, 2-methylthiazol-4-yl, 2-(1H-imidazol-2-yl),2-(1H-imidazol-4-yl) or 3-amino-1H-pyrazol-5-yl.
 13. The compound ofclaim 3, wherein Ar² is 2,4-difluorophenyl.
 14. The compound of claim 4,wherein Ar² is phenyl optionally substituted with one or more groupsindependently selected from halogen, OR¹⁰, NR¹⁰R¹¹, CN, NO₂,—OP(═O)(OR¹⁰)₂, C(═O)OR¹⁰, or Ar² is a heteroaryl selected from pyridyl,thiophenyl optionally substituted with alkyl, imidazolyl, and pyrazolyloptionally substituted with NR¹⁰R¹¹.
 15. The compound of claim 4,wherein Ar² is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,3,4-dimethylphenyl, 3,5-dimethylphenyl, 2-ethylphenyl, 3-ethylphenyl,4-t-butylphenyl, 2-chlorophenyl, 4-chlorophenyl, 3-fluorophenyl,4-fluorophenyl, 4-bromophenyl, 3,4-dichlorophenyl, 3-nitrophenyl,3-hydroxyphenyl, 3-(OPO₃H₂)-phenyl, 3-aminophenyl, 3-carboxyphenyl,3-cyanophenyl, 2-pyridyl, 3-pyridyl, 5-methylthiophen-2-yl,2-methylthiazol-4-yl, 2-(1H-imidazol-2-yl), 2-(1H-imidazol-4-yl) or3-amino-1H-pyrazol-5-yl.
 16. The compound of claim 4, wherein Ar² is2,4-difluorophenyl.
 17. The compound of claim 1, wherein W is S.
 18. Thecompound of claim 1, selected from the group consisting of:3-(5-(2,5-difluorophenyl)-2-phenyl-3-(5-phenyl-4H-1,2,4-triazol-3-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine;3-(5-(2,5-difluorophenyl)-2-phenyl-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine;and3-(3-(5-bromo-1,3,4-thiadiazol-2-yl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propan-1-amine;and salts thereof.
 19. A composition comprising a compound of claim 1,and a pharmaceutically acceptable carrier.